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.

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.

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.

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.

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.

Determining the potential clinical value of panel-based pharmacogenetic testing in patients with chronic pain or gastroesophageal reflux disease.

We aimed to determine the potential value of panel-based pharmacogenetic (PGx) testing in patients with chronic pain or gastroesophageal reflux disease (GERD) who underwent single-gene PGx testing to guide opioid or proton pump inhibitor (PPI) therapy, respectively. Of 448 patients included (chronic pain, n = 337; GERD, n = 111), mean age was 57 years, 68% were female, and 73% were white. Excluding opiates for the pain cohort and PPIs for the GERD cohort, 76.6% of patients with pain and 71.2% with GERD were prescribed at least one additional medication with a high level of PGx evidence, most commonly ondansetron or selective serotonin reuptake inhibitors. The most common genes that could inform PGx drug prescribing were CYP2C19, CYP2D6, CYP2C9, and SLCO1B1. Our findings suggest that patients with chronic pain or GERD are commonly prescribed drugs with a high level of evidence for a PGx-guided approach, supporting panel-based testing in these populations.

Trends in prescription opioid use and dose trajectories before opioid use disorder or overdose in US adults from 2006 to 2016: A cross-sectional study.

BACKGROUND: With governments' increasing efforts to curb opioid prescription use and limit dose below the Centers for Disease Control and Prevention (CDC)-recommended threshold of 90 morphine milligram equivalents per day, little is known about prescription opioid patterns preceding opioid use disorder (OUD) or overdose. This study aimed to determine prescribed opioid fills and dose trajectories in the year before an incident OUD or overdose diagnosis using a 2005-2016 commercial healthcare database. METHODS AND FINDINGS: This cross-sectional study identified individuals aged 18 to 64 years with incident OUD or overdose in the United States. We measured the prevalence of opioid prescription fills and trajectories of opioid morphine equivalent dose (MED) prescribed during the 12-month period before the diagnosis. Of 227,038 adults with incident OUD or overdose, 33.1% were aged 18 to 30 years, 52.9% were males, and 85.0% were metropolitan residents. Half (50.5%) of the patients had a diagnosis of chronic pain, 32.7% had depression, and 20.3% had anxiety. Overall, 79,747 (35.1%) patients filled no opioid prescription in the 12 months before OUD or overdose diagnosis, with the proportion significantly increasing between 2006 and 2016 (adjusted prevalence ratio, 1.86; 95% CI 1.79-1.93; P < 0.001). Patients without (versus with) prescribed opioids tended to be younger males and metropolitan and Northeast US residents. Of 145,609 patients who filled opioid prescriptions, 5 distinct prescribed daily dose trajectories preceding diagnosis emerged: consistent low dose (<3 mg MED, 34.6%), consistent moderate dose (20 mg MED, 27.3%), consistent high dose (150 mg MED, 15.0%), escalating dose (from <3 to 20 mg MED, 13.7%), and de-escalating dose (from 20 to <3mg MED, 9.4%). Overall, over two-thirds of patients with OUD or overdose with prescription opioids were prescribed a mean daily dose below 90 mg MED before diagnosis. Major limitations include the limited generalizability of the study findings and lack of information on out-of-pocket drug spending, race/ethnicity, and socioeconomic status of participants, which prevents analyses addressing these characteristics. CONCLUSIONS: In this study, we found that absence of opioid prescription fills in the year before incident OUD or overdose diagnosis was prevalent, and the majority of the patients received prescription opioid doses below the risk threshold of 90 mg MED. An increasing proportion of high-risk patients could be missed by current programs solely based on opioid prescribing and dispensing information in this new era of limited access to prescription opioids.

CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial.

PURPOSE: CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control. METHODS: Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS® measures. RESULTS: On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540). CONCLUSION: These data support the potential benefits of CYP2D6-guided pain management.

Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene-drug pairs across ambulatory care settings.

PURPOSE: Incorporating a patient's genotype into the clinical decision-making process is one approach to precision medicine. The University of Florida (UF) Health Precision Medicine Program is a pharmacist-led multidisciplinary effort that has led the clinical implementation of six gene-drug(s) pairs to date. This study focuses on the challenges encountered and lessons learned with implementing pharmacogenetic testing for three of these: CYP2D6-opioids, CYP2D6/CYP2C19-selective serotonin reuptake inhibitors, and CYP2C19-proton pump inhibitors within six pragmatic clinical trials at UF Health and partners. METHODS: We compared common measures collected within each of the pharmacogenetic implementations as well as solicited feedback from stakeholders to identify challenges, successes, and lessons learned. RESULTS: We identified several challenges related to trial design and implementation, and learned valuable lessons. Most notably, case discussions are effective for prescriber education, prescribers need clear concise guidance on genotype-based actions, having genotype results available at the time of the patient-prescriber encounter helps optimize the ability to act on them, children prefer noninvasive sample collection, and study participants are willing to answer patient-reported outcomes questionnaires if they are not overly burdensome, among others. CONCLUSION: The lessons learned from implementing three gene-drug pairs in ambulatory care settings will help shape future pharmacogenetic clinical trials and clinical implementations.

Pharmacogenetics: Using Genetic Information to Guide Drug Therapy.

Clinical pharmacogenetics, the use of genetic data to guide drug therapy decisions, is beginning to be used for medications commonly prescribed by family physicians. However, clinicians are largely unfamiliar with principles supporting clinical use of this type of data. For example, genetic variability in the cytochrome P450 2D6 drug metabolizing enzyme can alter the clinical effects of some opioid analgesics (e.g., codeine, tramadol), whereas variability in the CYP2C19 enzyme affects the antiplatelet agent clopidogrel. If testing is performed, patients who are ultrarapid or poor metabolizers of CYP2D6 should avoid codeine use (and possibly tramadol, hydrocodone, and oxycodone) because of the potential for increased toxicity or lack of effectiveness. Patients undergoing percutaneous coronary intervention for acute coronary syndromes who are known to be poor metabolizers of CYP2C19 should consider alternate antiplatelet therapy (e.g., ticagrelor, prasugrel). Some guidelines are available that address appropriate drug therapy changes, and others are in development. Additionally, a number of clinical resources are emerging to support family physicians in the use of pharmacogenetics. When used appropriately, pharmacogenetic testing can be a practical tool to optimize drug therapy and avoid medication adverse effects.

Design and development of a machine-learning-driven opioid overdose risk prediction tool integrated in electronic health records in primary care settings.

BACKGROUND: Integrating advanced machine-learning (ML) algorithms into clinical practice is challenging and requires interdisciplinary collaboration to develop transparent, interpretable, and ethically sound clinical decision support (CDS) tools. We aimed to design a ML-driven CDS tool to predict opioid overdose risk and gather feedback for its integration into the University of Florida Health (UFHealth) electronic health record (EHR) system. METHODS: We used user-centered design methods to integrate the ML algorithm into the EHR system. The backend and UI design sub-teams collaborated closely, both informed by user feedback sessions. We conducted seven user feedback sessions with five UF Health primary care physicians (PCPs) to explore aspects of CDS tools, including workflow, risk display, and risk mitigation strategies. After customizing the tool based on PCPs' feedback, we held two rounds of one-on-one usability testing sessions with 8 additional PCPs to gather feedback on prototype alerts. These sessions informed iterative UI design and backend processes, including alert frequency and reappearance circumstances. RESULTS: The backend process development identified needs and requirements from our team, information technology, UFHealth, and PCPs. Thirteen PCPs (male = 62%, White = 85%) participated across 7 user feedback sessions and 8 usability testing sessions. During the user feedback sessions, PCPs (n = 5) identified flaws such as the term "high risk" of overdose potentially leading to unintended consequences (e.g., immediate addiction services referrals), offered suggestions, and expressed trust in the tool. In the first usability testing session, PCPs (n = 4) emphasized the need for natural risk presentation (e.g., 1 in 200) and suggested displaying the alert multiple times yearly for at-risk patients. Another 4 PCPs in the second usability testing session valued the UFHealth-specific alert for managing new or unfamiliar patients, expressed concerns about PCPs' workload when prescribing to high-risk patients, and recommended incorporating the details page into training sessions to enhance usability. CONCLUSIONS: The final backend process for our CDS alert aligns with PCP needs and UFHealth standards. Integrating feedback from PCPs in the early development phase of our ML-driven CDS tool helped identify barriers and facilitators in the CDS integration process. This collaborative approach yielded a refined prototype aimed at minimizing unintended consequences and enhancing usability.

Deprescribing Strategies for Opioids and Benzodiazepines with Emphasis on Concurrent Use: A Scoping Review.

While the Food and Drug Administration's black-box warnings caution against concurrent opioid and benzodiazepine (OPI-BZD) use, there is little guidance on how to deprescribe these medications. This scoping review analyzes the available opioid and/or benzodiazepine deprescribing strategies from the PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases (01/1995-08/2020) and the gray literature. We identified 39 original research studies (opioids: n = 5, benzodiazepines: n = 31, concurrent use: n = 3) and 26 guidelines (opioids: n = 16, benzodiazepines: n = 11, concurrent use: n = 0). Among the three studies deprescribing concurrent use (success rates of 21-100%), two evaluated a 3-week rehabilitation program, and one assessed a 24-week primary care intervention for veterans. Initial opioid dose deprescribing rates ranged from (1) 10-20%/weekday followed by 2.5-10%/weekday over three weeks to (2) 10-25%/1-4 weeks. Initial benzodiazepine dose deprescribing rates ranged from (1) patient-specific reductions over three weeks to (2) 50% dose reduction for 2-4 weeks, followed by 2-8 weeks of dose maintenance and then a 25% reduction biweekly. Among the 26 guidelines identified, 22 highlighted the risks of co-prescribing OPI-BZD, and 4 provided conflicting recommendations on the OPI-BZD deprescribing sequence. Thirty-five states' websites provided resources for opioid deprescription and three states' websites had benzodiazepine deprescribing recommendations. Further studies are needed to better guide OPI-BZD deprescription.

Characterizing OPRM1 DNA methylation in prescription opioid users with chronic musculoskeletal pain.

Introduction: Many patients with chronic pain use prescription opioids. Epigenetic modification of the µ-opioid receptor 1 (OPRM1) gene, which codes for the target protein of opioids, may influence vulnerability to opioid abuse and response to opioid pharmacotherapy, potentially affecting pain outcomes. Objective: Our objective was to investigate associations of clinical and sociodemographic factors with OPRM1 DNA methylation in patients with chronic musculoskeletal pain on long-term prescription opioids. Methods: Sociodemographic variables, survey data (Rapid Estimate of Adult Health Literacy in Medicine-Short Form, Functional Comorbidity Index [FCI], PROMIS 43v2.1 Profile, Opioid Risk Tool, and PROMIS Prescription Pain Medication Misuse), and saliva samples were collected. The genomic DNA extracted from saliva samples were bisulfite converted, amplified by polymerase chain reaction, and processed for OPRM1-targeted DNA methylation analysis on a Pyrosequencing instrument (Qiagen Inc, Valencia, CA). General linear models were used to examine the relationships between the predictors and OPRM1 DNA methylation. Results: Data from 112 patients were analyzed. The best-fitted multivariable model indicated, compared with their counterparts, patients with > eighth grade reading level, degenerative disk disease, substance abuse comorbidity, and opioid use < 1 year (compared with >5 years), had average methylation levels that were 7.7% (95% confidence interval [CI] 0.95%, 14.4%), 11.7% (95% CI 2.7%, 21.1%), 21.7% (95% CI 10.7%, 32.5%), and 16.1% (95% CI 3.3%, 28.8%) higher than the reference groups, respectively. Methylation levels were 2.2% (95% CI 0.64%, 3.7%) lower for every 1 unit increase in FCI and greater by 0.45% (95% CI 0.08%, 0.82%) for every fatigue T score unit increase. Conclusions: OPRM1 methylation levels varied by several patient factors. Further studies are warranted to replicate these findings and determine potential clinical utility.

A randomized, cross-over trial of metoprolol succinate formulations to evaluate PK and PD end points for therapeutic equivalence.

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended-release (ER) tablets. We compared the pharmacokinetics (PKs) and pharmacodynamics of brand name versus two generic formulations (drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax ) in adults with hypertension. Participants were randomized to equal drug doses (50-150 mg/day) administered in one of two sequences (brand-drug1-brand-drug2 or brand-drug2-brand-drug1) and completed 24-h PK, digital heart rate (HR), ambulatory blood pressure (BP), and HR studies after taking each formulation for greater than or equal to 7 days. Metoprolol concentrations were determined by liquid chromatography tandem mass spectrometry, with noncompartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low-to-high frequency ratio was determined per quartile over the 24-h period. Thirty-six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK end points of area under the concentration-time curve and Cmax were similar between products; Tmax was 6.1 ± 3.6 for the brand versus 3.5 ± 4.9 for drug 1 (p = 0.019) and 9.6 ± 3.2 for drug 2 (p < 0.001). Among all 36 participants, 24-h BPs and HRs were similar between products. Mean 24-h HRV low-to-high ratio was also similar for drug 1 (2.04 ± 1.35), drug 2 (1.86 ± 1.35), and brand (2.04 ± 1.77), but was more sustained over time for the brand versus drug 1 (drug × quartile interaction p = 0.017). Differences in Tmax between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.

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.

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.

Advanced Liver Fibrosis Is Common in Patients With Type 2 Diabetes Followed in the Outpatient Setting: The Need for Systematic Screening.

OBJECTIVE: Assess the prevalence of nonalcoholic fatty liver disease (NAFLD) and of liver fibrosis associated with nonalcoholic steatohepatitis in unselected patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: A total of 561 patients with T2DM (age: 60 ± 11 years; BMI: 33.4 ± 6.2 kg/m2; and HbA1c: 7.5 ± 1.8%) attending primary care or endocrinology outpatient clinics and unaware of having NAFLD were recruited. At the visit, volunteers were invited to be screened by elastography for steatosis and fibrosis by controlled attenuation parameter (≥274 dB/m) and liver stiffness measurement (LSM; ≥7.0 kPa), respectively. Secondary causes of liver disease were ruled out. Diagnostic panels for prediction of advanced fibrosis, such as AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) index, were also measured. A liver biopsy was performed if results were suggestive of fibrosis. RESULTS: The prevalence of steatosis was 70% and of fibrosis 21% (LSM ≥7.0 kPa). Moderate fibrosis (F2: LSM ≥8.2 kPa) was present in 6% and severe fibrosis or cirrhosis (F3-4: LSM ≥9.7 kPa) in 9%, similar to that estimated by FIB-4 and APRI panels. Noninvasive testing was consistent with liver biopsy results. Elevated AST or ALT ≥40 units/L was present in a minority of patients with steatosis (8% and 13%, respectively) or with liver fibrosis (18% and 28%, respectively). This suggests that AST/ALT alone are insufficient as initial screening. However, performance may be enhanced by imaging (e.g., transient elastography) and plasma diagnostic panels (e.g., FIB-4 and APRI). CONCLUSIONS: Moderate-to-advanced fibrosis (F2 or higher), an established risk factor for cirrhosis and overall mortality, affects at least one out of six (15%) patients with T2DM. These results support the American Diabetes Association guidelines to screen for clinically significant fibrosis in patients with T2DM with steatosis or elevated ALT.

Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.

Trends in prior receipt of prescription opioid or adjuvant analgesics among patients with incident opioid use disorder or opioid-related overdose from 2006 to 2016.

BACKGROUND: With increasing efforts to scrutinize and reduce opioid prescribing, limited data exist on the recent trend in receipt of prescription pain medications before diagnosis of opioid use disorder (OUD) or opioid-related overdose (OD). METHODS: Using 2005-2016 Truven MarketScan Commercial Claims databases, we assessed trends in annual 1) incidence of OUD or OD and 2) prevalence of receipt of prescription opioids or four commonly-prescribed adjuvant analgesics among patients newly diagnosed with OUD/OD. Trends were examined in the overall sample and by 3 age groups, including youths (≤18 years), adults (19-64 years), and older adults (≥65 years). RESULTS: The incidence of diagnosed OUD or OD increased more than 3-fold from 4.99 to 23.81 per 10,000 persons from 2006 to 2016, with the highest increase (14.18-fold) seen in older adults, followed by adults (3.53-fold), and youths (0.16-fold). Between 2006 and 2016, the proportion of patients with incident OUD/OD who received anticonvulsant adjuvant analgesics in the year before diagnosis increased (from 23.4% to 34.3% [P-trend = .005]) whereas the proportion receiving high-dose prescriptions opioids decreased (from 45.5% to 34.8% [P-trend =< .001]). A decreasing trend was observed in general for tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors. DISCUSSION: In US commercially insured patients newly diagnosed with OUD/OD, receipt of high-dose opioid prescriptions preceding the diagnosis decreased over time, paralleled by increased use of anticonvulsants commonly prescribed for pain conditions. Further investigations are warranted to understand how prescribed and anticonvulsants contribute to the development of OUD/OD.

Clinical application of pharmacogenetics in pain management.

There is growing experience translating genomic data into clinical practice, as seen with the Implementing GeNomics In pracTicE (IGNITE) network. A primary example is the influence of CYP2D6 genotype on the beneficial and adverse effects of some opioids. Clinical recommendations exist to guide drug therapy based on CYP2D6 genotype for codeine, tramadol, oxycodone and hydrocodone, although the level of supporting evidence differs by drug. Limited evidence also supports the use of genetic data to guide other medications in chronic pain therapy, including tricyclic antidepressants and celecoxib. Pragmatic clinical trial data are needed in this area to better understand the impact of diverse populations, therapeutic interventions and clinical care environments on genotype-guided drug therapy for chronic pain.