Clinical and Adverse Outcomes Associated With Concomitant Use of CYP2D6-Metabolized Opioids With Antidepressants in Older Nursing Home Residents : A Target Trial Emulation Study.

BACKGROUND: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents. OBJECTIVE: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs). DESIGN: Retrospective cohort study using a target trial emulation framework. SETTING: 100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021. PARTICIPANTS: Long-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use. INTERVENTION: Initiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more. MEASUREMENTS: Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting. RESULTS: Among 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose. LIMITATION: Findings are generalizable to NH populations only. CONCLUSION: Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents. PRIMARY FUNDING SOURCE: National Institute on Aging.

Use of CYP2D6 Inhibitors with CYP2D6 Opioids: Association with Emergency Department Visits for Pain.

Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6-dependent opioids while on CYP2D6-inhibitor antidepressants vs. antidepressants that do not inhibit CYP2D6. This retrospective cohort study included adult patients prescribed CYP2D6-dependent opioids utilizing electronic health records data from the University of Florida Health (2015-2021). The association between ED visits and inhibitor exposure was tested using multivariable logistic regression. The primary analysis had 12,118 patients (72% female; mean (SD) age, 55 (13.4)) in the hydrocodone/tramadol/codeine cohort and 5,547 patients (64% female; mean (SD) age, 53.6 (14.2)) in the oxycodone cohort. Hydrocodone/tramadol/codeine-treated patients exposed to CYP2D6-inhibitor antidepressants (n = 7,043) had a higher crude rate of pain-related ED visits than those taking other antidepressants (n = 5,075) (3.28% vs. 1.87%), with an adjusted odds ratio (aOR) of 1.75 (95% CI: 1.36 to 2.24). Similarly, in the oxycodone cohort, CYP2D6-inhibitor antidepressant-exposed individuals (n = 3,206) had a higher crude rate of ED visits than individuals exposed to other antidepressants (n = 2,341) (5.02% vs. 3.37%), with aOR of 1.70 (95% CI: 1.27-2.27). Similar findings were observed in secondary and sensitivity analyses. Our findings suggest patients with concomitant use of hydrocodone/tramadol/codeine or oxycodone and CYP2D6 inhibitors have more frequent ED visits for pain, which may be due to inadequate pain control.

Short- and long-term safety of discontinuing chronic opioid therapy among older adults with Alzheimer's disease and related dementia.

BACKGROUND: Limited evidence exists on the short- and long-term safety of discontinuing versus continuing chronic opioid therapy (COT) among patients with Alzheimer's disease and related dementias (ADRD). METHODS: This cohort study was conducted among 162,677 older residents with ADRD and receipt of COT using a 100% Medicare nursing home sample. Discontinuation of COT was defined as no opioid refills for ≥90 days. Primary outcomes were rates of pain-related hospitalisation, pain-related emergency department visit, injury, opioid use disorder (OUD) and opioid overdose (OD) measured by diagnosis codes at quarterly intervals during 1- and 2-year follow-ups. Poisson regression models were fit using generalised estimating equations with inverse probability of treatment weights to model quarterly outcome rates between residents who discontinued versus continued COT. RESULTS: The study sample consisted of 218,040 resident episodes with COT; of these episodes, 180,916 residents (83%) continued COT, whereas 37,124 residents (17%) subsequently discontinued COT. Discontinuing (vs. continuing) COT was associated with higher rates of all outcomes in the first quarter, but these associations attenuated over time. The adjusted rates of injury, OUD and OD were 0, 69 and 60% lower at the 1-year follow-up and 11, 81 and 79% lower at the 2-year follow-up, respectively, for residents who discontinued versus continued COT, with no difference in the adjusted rates of pain-related hospitalisations or emergency department visits. CONCLUSIONS: The rates of adverse outcomes were higher in the first quarter but lower or non-differential at 1-year and 2-year follow-ups between COT discontinuers versus continuers among older residents with ADRD.

Sociodemographic Characteristics of Adverse Event Reporting in the USA: An Ecologic Study.

INTRODUCTION: The Food and Drug Administration Adverse Event Reporting System (FAERS) is a vital source of new drug safety information, but whether adverse event (AE) information collected from these systems adequately captures experiences of the overall United States (US) population is unknown. OBJECTIVE: To examine determinants of consumer AE reporting in the USA. METHODS: Five-year AE reporting rate per 100,000 residents per US county were calculated, mapped, and quartiled for AE reports received directly from consumers between 2011 and 2015. Associations between county-level sociodemographic factors obtained from County Health Rankings and AE reporting rates were evaluated using negative binomial regression. RESULTS: Reporting rates were variable across US counties with > 17.6 reports versus ≤ 5.5 reports/100,000 residents in the highest and lowest reporting quartile, respectively. Controlling for drug utilization, counties with higher reporting rates had higher proportions of individuals age ≥ 65 years (e.g., 2.4% reporting increase per 1% increase in individuals age > 65, incidence rate ratio (IRR): 1.024, 95% confidence interval (CI): 1.017-1.030), higher proportions of females (IRR: 1.027, 95% CI 1.012-1.043), uninsured (IRR: 1.009, 95% CI 1.005-1.013), higher median log household incomes (IRR: 1.897, 95% CI 1.644-2.189) and more mental health providers per 100,000 residents (IRR: 1.003, 95% CI 1.001-1.004). Lower reporting was observed in counties with higher proportions of individuals age ≤ 18 years (IRR: 0.966, 95% CI 0.959-0.974), American Indian or Alaska Native individuals (IRR: 0.991, 95% CI 0.986-0.996), individuals not proficient in English (IRR: 0.978, 95% CI 0.965-0.991), and individuals residing in rural areas within a county (IRR: 0.998, 95% CI 0.997-0.998). CONCLUSIONS: Observed variations in consumer AE reporting may be related to sociodemographic factors and healthcare access. Because these factors may also correspond to AE susceptibility, voluntary AE reporting systems may be suboptimal for capturing emerging drug safety concerns among more vulnerable populations.

Prevalence and trend of central nervous system-active medication polypharmacy among US commercially insured adults with vs without early-onset dementia: a multi-year cross-sectional study.

BACKGROUND: Limited data exist on the prevalence and trend of central nervous system (CNS)-active medication polypharmacy among adults with early-onset dementia (EOD) and whether these estimates differ for adults without EOD but with chronic pain, depression, or epilepsy, conditions managed by CNS-active medications. METHODS: A multi-year, cross-sectional study using 2012-2021 MarketScan Commercial Claims data was conducted among adults aged 30 to 64 years with EOD and those without EOD but having a diagnosis of chronic pain, depression, or epilepsy as comparison groups. For each disease cohort, the primary outcome was CNS-active medication polypharmacy defined as concurrent use of ≥ 3 CNS-active medications on the US Beers Criteria list that overlapped for > 30 consecutive days during 12 months following a randomly selected medical encounter with the disease diagnosis. A separate multivariate modified Poisson regression model was used to estimate time trends in CNS polypharmacy in each disease cohort. Differences in trend estimates between EOD and non-EOD disease cohorts were examined by an interaction between EOD status and yearly time. RESULTS: From 2013 to 2020, the annual crude prevalence of CNS polypharmacy was higher among adults with EOD (21.2%-25.0%) than adults with chronic pain (5.1%-5.9%), depression (14.8%-21.7%), or epilepsy (20.0%-22.3%). The adjusted annual prevalence of CNS polypharmacy among patients with EOD did not significantly change between 2013 and 2020 (adjusted prevalence rate ratio [aPRR], 0.94; 95% CI, 0.88-1.01), whereas a significant decreasing trend was observed among non-EOD cohorts with chronic pain (aPRR, 0.66; 95% CI, 0.63-0.69), depression (aPRR, 0.81; 95% CI, 0.77-0.85), and epilepsy (aPRR, 0.86; 95% CI, 0.83-0.89). The interaction analysis indicated that patients with epilepsy and depression (vs with EOD) had a decreasing probability of CNS-active medication polypharmacy over time (aPRR, 0.98 [95% CI, 0.98-0.99]; P < .001 for interaction for both conditions). CONCLUSIONS: The prevalence of CNS polypharmacy among US commercially insured adults with EOD (vs without) was higher and remained unchanged from 2013 to 2021. Medication reviews of adults with EOD and CNS polypharmacy are needed to ensure that benefits outweigh risks associated with combined use of these treatments.

Pain intensity, physical function, and depressive symptoms associated with discontinuing long-term opioid therapy in older adults with Alzheimer's disease and related dementias.

INTRODUCTION: Limited evidence exists on the associations of discontinuing versus continuing long-term opioid therapy (LTOT) with pain intensity, physical function, and depression among patients with Alzheimer's disease and related dementias (ADRD). METHODS: A cohort study among 138,059 older residents with mild-to-moderate ADRD and receipt of LTOT was conducted using a 100% Medicare nursing home sample. Discontinuation of LTOT was defined as no opioid refills for ≥ 60 days. Outcomes were worsening pain, physical function, and depression from baseline to quarterly assessments during 1- and 2-year follow-ups. RESULTS: The adjusted odds of worsening pain and depressive symptoms were 29% and 5% lower at the 1-year follow-up and 35% and 9% lower at the 2-year follow-up for residents who discontinued versus continued LTOT, with no difference in physical function. DISCUSSION: Discontinuing LTOT was associated with lower short- and long-term worsening pain and depressive symptoms than continuing LTOT among older residents with ADRD. HIGHLIGHTS: Discontinuing long-term opioid therapy (LTOT) was associated with lower short- and long-term worsening pain. Discontinuing LTOT was related to lower short- and long-term worsening depression. Discontinuing LTOT was not associated with short- and long-term physical function.

Experimental Revelation of Surface and Bulk Lattices in Faceted Cu2 O Crystals.

Semiconductor crystals have generally shown facet-dependent electrical, photocatalytic, and optical properties. These phenomena have been proposed to result from the presence of a surface layer with bond-level deviations. To provide experimental evidence of this structural feature, synchrotron X-ray sources are used to obtain X-ray diffraction (XRD) patterns of polyhedral cuprous oxide crystals. Cu2 O rhombic dodecahedra display two distinct cell constants from peak splitting. Peak disappearance during slow Cu2 O reduction to Cu with ammonia borane differentiates bulk and surface layer lattices. Cubes and octahedra also show two peak components, while diffraction peaks of cuboctahedra are comprised of three components. Temperature-varying lattice changes in the bulk and surface regions also show shape dependence. From transmission electron microscopy (TEM) images, slight plane spacing deviations in surface and inner crystal regions are measured. Image processing provides visualization of the surface layer with depths of about 1.5-4 nm giving dashed lattice points instead of dots from atomic position deviations. Close TEM examination reveals considerable variation in lattice spot size and shape for different particle morphologies, explaining why facet-dependent properties are emerged. Raman spectrum reflects the large bulk and surface lattice difference in rhombic dodecahedra. Surface lattice difference can change the particle bandgap.

Trends in Dietary Vitamin A Intake Among US Adults by Race and Ethnicity, 2003-2018.

This study uses data from the 2003-2004 to 2017-2018 National Health and Nutrition Examination Surveys (NHANES) to assess whether a difference exists in dietary vitamin A intake as a marker of consumption of vitamin A­rich foods among Black, Hispanic, and White adults in the US.

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.

Perioperative Use of Gabapentinoids and Risk for Postoperative Long-Term Opioid Use in Older Adults Undergoing Total Knee or Hip Arthroplasty.

BACKGROUND: Gabapentinoids are recommended by guidelines as a component of multimodal analgesia to manage postoperative pain and reduce opioid use. It remains unknown whether perioperative use of gabapentinoids is associated with a reduced or increased risk of postoperative long-term opioid use (LTOU) after total knee or hip arthroplasty (TKA/THA). METHODS: Using Medicare claims data from 2011 to 2018, we identified fee-for-service beneficiaries aged ≥ 65 years who were hospitalized for a primary TKA/THA and had no LTOU before the surgery. Perioperative use of gabapentinoids was measured from 7 days preadmission through 7 days postdischarge. Patients were required to receive opioids during the perioperative period and were followed from day 7 postdischarge for 180 days to assess postoperative LTOU (ie, ≥90 consecutive days). A modified Poisson regression was used to estimate the relative risk (RR) of postoperative LTOU in patients with versus without perioperative use of gabapentinoids, adjusting for confounders through propensity score weighting. RESULTS: Of 52,788 eligible Medicare older beneficiaries (mean standard deviation [SD] age 72.7 [5.3]; 62.5% females; 89.7% White), 3,967 (7.5%) received gabapentinoids during the perioperative period. Postoperative LTOU was 3.8% in patients with and 4.0% in those without perioperative gabapentinoids. After adjusting for confounders, the risk of postoperative LTOU was similar comparing patients with versus without perioperative gabapentinoids (RR = 1.07; 95% confidence interval [CI] = 0.91-1.26, P = .408). Sensitivity and bias analyses yielded consistent results. CONCLUSION: Among older Medicare beneficiaries undergoing a primary TKA/THA, perioperative use of gabapentinoids was not associated with a reduced or increased risk for postoperative LTOU.

Trajectories of prescription opioid dose and risk of opioid-related adverse events among older Medicare beneficiaries in the United States: A nested case-control study.

BACKGROUND: Despite the rising number of older adults with medical encounters for opioid misuse, dependence, and poisoning, little is known about patterns of prescription opioid dose and their association with risk for opioid-related adverse events (ORAEs) in older patients. The study aims to compare trajectories of prescribed opioid doses in 6 months preceding an incident ORAE for cases and a matched control group of older patients with chronic noncancer pain (CNCP). METHODS AND FINDINGS: We conducted a nested case-control study within a cohort of older (≥65 years) patients diagnosed with CNCP who were new users of prescription opioids, assembled using a 5% national random sample of Medicare beneficiaries from 2011 to 2018. From the cohort with a mean follow-up of 2.3 years, we identified 3,103 incident ORAE cases with ≥1 opioid prescription in 6 months preceding the event, and 3,103 controls matched on sex, age, and time since opioid initiation. Key exposure was trajectories of prescribed opioid morphine milligram equivalent (MME) daily dosage over 6 months before the incident ORAE or matched controls. Among the cases and controls, 2,192 (70.6%) were women, and the mean (SD) age was 77.1 (7.1) years. Four prescribed opioid trajectories before the incident ORAE diagnosis or matched date emerged: gradual dose discontinuation (from ≤3 to 0 daily MME, 1,456 [23.5%]), gradual dose increase (from 0 to >3 daily MME, 1,878 [30.3%]), consistent low dose (between 3 and 5 daily MME, 1,510 [24.3%]), and consistent moderate dose (>20 daily MME, 1,362 [22.0%]). Few older patients (<5%) were prescribed a mean daily dose of ≥90 daily MME during 6 months before diagnosis or matched date. Patients with gradual dose discontinuation versus those with a consistent low dose, moderate dose, and increase dose were more likely to be younger (65 to 74 years), Midwest US residents, and receiving no low-income subsidy. Compared to patients with gradual dose discontinuation, those with gradual dose increase (adjusted odds ratio [aOR] = 3.4; 95% confidence interval (CI) 2.8 to 4.0; P < 0.001), consistent low dose (aOR = 3.8; 95% CI 3.2 to 4.6; P < 0.001), and consistent moderate dose (aOR = 8.5; 95% CI 6.8 to 10.7; P < 0.001) had a higher risk of ORAE, after adjustment for covariates. Our main findings remained robust in the sensitivity analysis using a cohort study with inverse probability of treatment weighting analyses. Major limitations include the limited generalizability of the study findings and lack of information on illicit opioid use, which prevents understanding the clinical dose threshold level that increases the risk of ORAE in older adults. CONCLUSIONS: In this sample of older patients who are Medicare beneficiaries, 4 prescription opioid dose trajectories were identified, with most prescribed doses below 90 daily MME within 6 months before ORAE or matched date. An increased risk for ORAE was observed among older patients with a gradual increase in dose or among those with a consistent low-to-moderate dose of prescribed opioids when compared to patients with opioid dose discontinuation. Whether older patients are susceptible to low opioid doses warrants further investigations.

Concurrent use of prescription gabapentinoids with opioids and risk for fall-related injury among older US Medicare beneficiaries with chronic noncancer pain: A population-based cohort study.

BACKGROUND: Gabapentinoids are increasingly prescribed to manage chronic noncancer pain (CNCP) in older adults. When used concurrently with opioids, gabapentinoids may potentiate central nervous system (CNS) depression and increase the risks for fall. We aimed to investigate whether concurrent use of gabapentinoids with opioids compared with use of opioids alone is associated with an increased risk of fall-related injury among older adults with CNCP. METHODS AND FINDINGS: We conducted a population-based cohort study using a 5% national sample of Medicare beneficiaries in the United States between 2011 and 2018. Study sample consisted of fee-for-service (FFS) beneficiaries aged ≥65 years with CNCP diagnosis who initiated opioids. We identified concurrent users with gabapentinoids and opioids days' supply overlapping for ≥1 day and designated first day of concurrency as the index date. We created 2 cohorts based on whether concurrent users initiated gabapentinoids on the day of opioid initiation (Cohort 1) or after opioid initiation (Cohort 2). Each concurrent user was matched to up to 4 opioid-only users on opioid initiation date and index date using risk set sampling. We followed patients from index date to first fall-related injury event ascertained using a validated claims-based algorithm, treatment discontinuation or switching, death, Medicare disenrollment, hospitalization or nursing home admission, or end of study, whichever occurred first. In each cohort, we used propensity score (PS) weighted Cox models to estimate the adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of fall-related injury, adjusting for year of the index date, sociodemographics, types of chronic pain, comorbidities, frailty, polypharmacy, healthcare utilization, use of nonopioid medications, and opioid use on and before the index date. We identified 6,733 concurrent users and 27,092 matched opioid-only users in Cohort 1 and 5,709 concurrent users and 22,388 matched opioid-only users in Cohort 2. The incidence rate of fall-related injury was 24.5 per 100 person-years during follow-up (median, 9 days; interquartile range [IQR], 5 to 18 days) in Cohort 1 and was 18.0 per 100 person-years during follow-up (median, 9 days; IQR, 4 to 22 days) in Cohort 2. Concurrent users had similar risk of fall-related injury as opioid-only users in Cohort 1(aHR = 0.97, 95% CI 0.71 to 1.34, p = 0.874), but had higher risk for fall-related injury than opioid-only users in Cohort 2 (aHR = 1.69, 95% CI 1.17 to 2.44, p = 0.005). Limitations of this study included confounding due to unmeasured factors, unavailable information on gabapentinoids' indication, potential misclassification, and limited generalizability beyond older adults insured by Medicare FFS program. CONCLUSIONS: In this sample of older Medicare beneficiaries with CNCP, initiating gabapentinoids and opioids simultaneously compared with initiating opioids only was not significantly associated with risk for fall-related injury. However, addition of gabapentinoids to an existing opioid regimen was associated with increased risks for fall. Mechanisms for the observed excess risk, whether pharmacological or because of channeling of combination therapy to high-risk patients, require further investigation. Clinicians should consider the risk-benefit of combination therapy when prescribing gabapentinoids concurrently with opioids.

Discontinuation of Long-Term Opioid Therapy in Patients With Versus Without Dementia.

INTRODUCTION: Discontinuation of long-term opioid therapy has increased in recent years, but whether this trend extends to patients with Alzheimer disease and related dementia remains unclear. METHODS: Medicare data from 2011 to 2018 were analyzed to compare the trends in the use and discontinuation of long-term opioid therapy between patients with and without Alzheimer disease and related dementia who had chronic noncancer pain. Outcome measures were annual proportions of (1) patients who received long-term opioid therapy and (2) long-term opioid therapy users who subsequently discontinued opioids for ≥30, 60, or 90 days during 12-month follow-up. All analyses were performed in 2021. RESULTS: The use of long-term opioid therapy decreased from 2011 to 2017 in both patients with and without Alzheimer disease and related dementia. In long-term opioid therapy users, discontinuation of opioids for ≥30, 60, and 90 days increased by 8% (95% CI=1.04, 1.12, p<0.001), 13% (95% CI=1.06, 1.20, p<0.001), and 18% (95% CI=1.10, 1.28, p<0.001), respectively, between 2011 and 2017 among patients with Alzheimer disease and related dementia, whereas the proportion was largely declining or unchanged among patients without the condition. Differences in long-term opioid therapy discontinuation by Alzheimer disease status widened over time (p<0.01 for interaction). CONCLUSIONS: Discontinuation of long-term opioid therapy was consistently higher in patients with than in patients without Alzheimer disease and related dementia, with the gap between the 2 groups widening over time. The reasons for these differences and the risk-benefit of increased long-term opioid therapy discontinuation among patients with Alzheimer disease and related dementia warrant further investigation.

Generalizability and accuracy of IBM MarketScan health risk assessment instrument data for augmentation of commercial claims data.

PURPOSE: We evaluated the generalizability and accuracy of the IBM® MarketScan® Health Risk Assessment (HRA) data to assess its suitability as supplement to linked claims data. METHODS: We identified adult private insurance enrollees in the IBM® MarketScan® Commercial Claims & Encounters (CC&E) and HRA databases between 2012 and 2017. In the claims data, for each enrollee, we sampled the first calendar year with continuous enrollment indicating full capture of claims data and extracted linked HRA survey data if available. We compared HRA participants and non-participants considering demographics, prevalences of chronic conditions, and healthcare utilization. Including the subsample with HRA data only, we estimated the negative predictive value (NPV) of obesity and smoking reported in the HRA against diagnosis code in the claims data. RESULTS: Between 2012 and 2017, 2 693 444 and 31 450 000 of HRA and non-HRA participants were included in the study, respectively. Chronic diseases were similarly distributed between the two populations, with hypertension and hyperlipidemia representing the highest prevalence difference (1.4%). The two samples showed similar healthcare utilization. The proportion of false-negatives for obesity and smoking information when relying on the HRA data compared to patients with positive diagnosis based on claims data was low (<1%). Prevalence estimates of both variables were similar to national estimates. CONCLUSION: Our findings suggest that the overall HRA population may represent the overall claims population and HRA provides certain data elements with satisfactory accuracy.

Concurrent Use of Prescription Opioids and Gabapentinoids in Older Adults.

INTRODUCTION: Concurrent use of prescription opioids with gabapentinoids may pose risks of serious drug interactions. Yet, little is known about the trends in and patient characteristics associated with concurrent opioid-gabapentinoid use among older Medicare opioid users with chronic noncancer pain. METHODS: A cross-sectional study was conducted among Medicare older beneficiaries (aged ≥65 years) with chronic noncancer pain who filled ≥1 opioid prescription within 3 months after a randomly selected chronic noncancer pain diagnosis (index date) in a calendar year between 2011 and 2018. Patient characteristics were measured in the 6-month baseline before the index date, and concurrent opioid-gabapentinoid use for ≥1 day was measured in the 3-month follow-up after the index date. Multivariable modified Poisson regression hwas used to assess the trends and characteristics of concurrent opioid-gabapentinoid use. Analyses were conducted from January to June 2021. RESULTS: Among 464,721 eligible older beneficiaries with chronic noncancer pain and prescription opioids, the prevalence of concurrent opioid-gabapentinoid use increased from 17.0% in 2011 to 23.5% in 2018 (adjusted prevalence ratio=1.48, 95% CI=1.45, 1.53). Concurrent users versus opioid-only users tended to be non-Black, low-income subsidy recipients, and Southern residents. The clinical factors associated with concurrent opioid-gabapentinoid use included having a diagnosis of neuropathic pain, polypharmacy, and risk factors for opioid-related adverse events. CONCLUSIONS: Concurrent opioid-gabapentinoid use among older Medicare beneficiaries with chronic noncancer pain and prescription opioids has increased significantly between 2011 and 2018. Future studies are warranted to investigate the impact of concurrent use on outcomes in older patients. Interventions that reduce inappropriate concurrent use may target older patients with identified characteristics.

Uncontrolled Pain and Risk for Depression and Behavioral Symptoms in Residents With Dementia.

OBJECTIVES: Limited cohort studies have assessed the association between uncontrolled pain and risk for behavioral and psychological symptoms of dementia (BPSDs). We conducted a longitudinal cohort study to examine whether associations exist between uncontrolled pain and risk for 2 common BPSDs-depression and behavioral symptoms-among long-term care (LTC) residents with Alzheimer disease and related dementia (ADRD). DESIGN: This retrospective cohort study analyzed quarterly data from the 5% Medicare sample linked to Minimum Data Set (MDS) 3.0 between January 1, 2011, and December 31, 2015. SETTING AND PARTICIPANTS: LTC residents aged 50 years or older with ADRD who had chronic pain and at least 2 quarterly MDS 3.0 assessments. METHODS: LTC residents were followed up quarterly from first observed quarterly MDS 3.0 until first outcome event or last observed quarterly MDS 3.0. Uncontrolled pain was defined as numerical rating scale >4, verbal descriptor scale of moderate or severe pain, or ≥1 pain indicators on the Checklist of Nonverbal Pain Indicators. Depression was defined as ≥10 on the Patient Health Questionnaire 9; behavioral symptoms were defined as the presence of psychotic (delusions or hallucinations) or disruptive behaviors (rejection of care, or physical, verbal, or other aggressive behaviors). Generalized linear models (GLMs) with marginal structural modeling (MSM) stabilized weights were used to examine uncontrolled pain and outcome risk. RESULTS: The incidence rate of depression and behavioral symptoms during follow-up was 9.4 and 23.1 per 100 resident-years, respectively. Results from the MSM-GLMs showed that LTC residents with uncontrolled pain had a higher risk than those with controlled pain for developing depression [hazard ratio 1.67, 95% confidence interval (CI) 1.54-1.81] and behavioral symptoms (hazard ratio 1.28, 95% CI 1.19-1.37). CONCLUSIONS AND IMPLICATIONS: Uncontrolled pain was associated with elevated risk for depressive and behavioral symptoms in dementia, underscoring the importance of pain assessment and control among LTC residents with ADRD.

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes.

OBJECTIVE: Emerging data from animal and human pilot studies suggest potential benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA) on lung function. We aimed to assess the association of GLP-1RA and chronic lower respiratory disease (CLRD) exacerbation in a population with comorbid type 2 diabetes (T2D) and CLRD. RESEARCH DESIGN AND METHODS: A new-user active-comparator analysis was conducted with use of a national claims database of beneficiaries with employer-sponsored health insurance spanning 2005-2017. We included adults with T2D and CLRD who initiated GLP-1RA or dipeptidyl peptidase 4 inhibitors (DPP-4I) as an add-on therapy to their antidiabetes regimen. The primary outcome was time to first hospital admission for CLRD. The secondary outcome was a count of any CLRD exacerbation associated with an inpatient or outpatient visit. We estimated incidence rates using inverse probability of treatment weighting for each study group and compared via risk ratios. RESULTS: The study sample consisted of 4,150 GLP-1RA and 12,540 DPP-4I new users with comorbid T2D and CLRD. The adjusted incidence rate of first CLRD admission during follow-up was 10.7 and 20.3 per 1,000 person-years for GLP-1RA and DPP-4I users, respectively, resulting in an adjusted hazard ratio of 0.52 (95% CI 0.32-0.85). For the secondary outcome, the adjusted incidence rate ratio was 0.70 (95% CI 0.57-0.87). CONCLUSIONS: GLP-1RA users had fewer CLRD exacerbations in comparison with DPP-4I users. Considering both plausible mechanistic pathways and this real-world evidence, potential beneficial effects of GLP-1RA may be considered in selection of an antidiabetes treatment regimen. Randomized clinical trials are warranted to confirm our findings.

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.

Utilization Patterns of Skeletal Muscle Relaxants Among Commercially Insured Adults in the United States from 2006 to 2018.

OBJECTIVE: To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults in the United States. METHODS: We used the MarketScan Research Database to identify a cohort of adults 18 to 64 years who had ≥2-year continuous enrollment between 2005 and 2018. We estimated the prevalence of SMR treatment using a repeated cross-sectional design and derived treatment duration using the Kaplan-Meier method. Analyses were stratified by age group, sex, geographic region, individual SMR agent, and musculoskeletal disorder. RESULTS: 48.7 million individuals were included. Treatment prevalence ranged from 61.5 to 68.3 per 1,000. About one-third of users did not have a preceding musculoskeletal disorder diagnosis. Cyclobenzaprine was the dominant agent accounting for >50% of prescriptions. The considerable growth in the use of baclofen, tizanidine, and methocarbamol paralleled with a decline in carisoprodol and metaxalone use. The prevalence was highest in the South while lowest in the Northeast. The median treatment duration was 14 days with 4.0%, 1.9%, and 1.0% of individuals using SMRs for more than 90, 180, and 365 days, respectively. Compared with cyclobenzaprine, patients initiating baclofen, tizanidine, and carisoprodol had longer treatment duration. CONCLUSIONS: SMRs are widely used in the United States. Their use slightly increased in recent years, but trends varied among individual agents, patient groups, and geographic regions. Despite limited evidence to support efficacy, a sizable number of U.S. adults used SMRs for long-term and off-label conditions. Further study is needed to understand determinants of treatment as well as outcomes associated with such use.