Matching study design to prescribing intention: The prevalent new-user design for studying abuse-deterrent formulations of opioids.

PURPOSE: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by "indication" are important considerations in ADF post-marketing studies. METHODS: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. RESULTS: We identified 8415 (NC claims) and 147 978 (MarketScan) ADF, and 10 114 (NC claims) and 232 028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64%-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. CONCLUSIONS: Careful consideration of the study design, comparator choice, and confounding by "indication" is crucial when examining ADF opioid use-related outcomes.

Characterization of gabapentin use in Kentucky after reclassification as a Schedule V controlled substance.

BACKGROUND: Owing to increasing concern over the potential for gabapentin misuse, gabapentin was reclassified as a schedule V controlled substance in Kentucky (July 2017). OBJECTIVE: This study aimed to characterize gabapentin use among Kentucky residents in the first year after its scheduling. METHODS: This study used Kentucky All Schedule Prescription Electronic Reporting data (2018). Gabapentin use was defined as having at least 1 dispensed gabapentin prescription, and high-dose gabapentin use was defined as an average daily dose of more than 3600 mg at the patient level. The prevalence of gabapentin use, concurrent use of gabapentin with opioid analgesics (OAs) (gabapentin-OA), and gabapentin with OAs and benzodiazepines (BDZs) (gabapentin-OA-BDZ) were assessed. Estimated prevalence rate ratio and its 95% CI were reported to compare gabapentin use rates across different demographic groups. RESULTS: A total of 16% of all 2018 controlled substance prescriptions were for gabapentin, and approximately 20% of Kentucky residents with controlled substance prescriptions received gabapentin at least once in 2018. The overall prevalence of gabapentin use was 63 per 1000 residents, with the highest rates among residents aged 55-64 years (126.9 per 1000). The prevalence of gabapentin use was higher in females (74.6 per 1000) versus males (50.6 per 1000) and in residents living in the Appalachian region (88.57 per 1000) versus Central (51.78 per 1000) and Delta (66.41 per 1000) regions. Among gabapentin users, 1% were high-dose users; 27.4% and 11.9% received gabapentin-OA or gabapentin-OA-BDZ concurrently, respectively. As the average daily dose increased from less than 900 mg to high-dose, the percentage of concurrent gabapentin-OA use increased from 13.4% to 50.7%. CONCLUSION: Gabapentin is widely prescribed in Kentucky, with higher rates of use observed in females, those older than 55 years and individuals living in the Appalachian region. Concurrent use of gabapentin and OAs is common, especially in those receiving high-dose gabapentin. Future studies are needed to assess the risks associated with gabapentin use.

Kentucky pharmacists' perceptions regarding provision of hormonal contraception.

BACKGROUND: Although Kentucky pharmacists recently gained authority to provide protocol-driven care for 13 conditions, provision of prescription hormonal contraception (HC) services is not currently authorized. A board-approved protocol allowing for provision of nonprescription over-the-counter (OTC) emergency contraception (EC) was recently approved by the Kentucky Board of Pharmacy but has yet to be implemented. OBJECTIVES: The objectives of this study were (1) to assess Kentucky pharmacists' interest in providing prescription HC and OTC EC services via protocol and (2) to identify perceived benefits/barriers regarding provision of prescription HC. METHODS: An online questionnaire was disseminated electronically to a convenience sample of Kentucky pharmacists. The questionnaire collected (1) demographic information, (2) opinions regarding provision of prescription HC and OTC EC, and (3) perceived benefits and barriers regarding provision of prescription HC. For analysis, responses were limited to pharmacists in community-based practice. McNemar's test was used to identify statistically significant differences in support by dosage form. In addition, a multivariable logistic regression model was used to examine associations between demographic factors and support for pharmacist provision of prescription HC. RESULTS: We received 151 responses from community-based pharmacists. Support for provision of prescription HC was highest for oral (61%) and transdermal (54%) forms. We found no statistically significant differences in support among demographic factors other than number of years in practice, with more recent graduates being at higher odds of support. In addition, time, reimbursement, training, and belief in the need for pelvic exams were the most commonly cited barriers to implementation. With regard to OTC EC provision, pharmacists were largely supportive (62%) and confident in their abilities. CONCLUSIONS: Community-based pharmacists in Kentucky are supportive of provision of oral, vaginal, and transdermal prescription HC as well as OTC EC via protocol. Barriers, including time, reimbursement, training, and belief in the need for pelvic exams, should be addressed to increase support for prescription HC provision.

Clinical characteristics and comorbidities in adult-onset Still's disease using a large US administrative claims database.

OBJECTIVES: We aimed to describe clinical characteristics, treatment patterns and major comorbidities of a US-based adult-onset Still's disease (AOSD) cohort. METHODS: Administrative claims data from Truven MarketScan were collected from 2009 to 2015. An AOSD case was defined as ≥1 M06.1 International Classification of Diseases 10th revision (ICD-10) medical claim code. We extracted data for the AOSD cohort (n = 106) and 1:5 matched controls (n = 530) without AOSD. Outcomes of interest and a novel claims-based set of Yamaguchi criteria were identified by relevant ICD 9th revision (ICD-9) and ICD-10 codes. Bivariate descriptive analyses were conducted on all variables. Comorbidity rates and rate ratios were calculated in AOSD cases and matched controls. Statistical significance of cohort differences was determined to compare AOSD cases and matched controls. RESULTS: The AOSD cohort, with a mean age of 43.08 (standard deviation, s.d. 13.9) years and with female predominance (68.9%) was observed over a mean of 750.12 (637.6) days. A total of 35.9% of AOSD patients fulfilled claims-based Yamaguchi criteria compared with 0.4% matched controls (P< 0.05). We identified severe AOSD-related complications, including macrophage activation syndrome (4.7%) and acute respiratory distress syndrome (12.3%). Treatment commonly involved systemic glucocorticoids (62.2%), MTX (51%) and anakinra (24.5%). Compared with matched controls, serious infections were significantly increased (rate ratio 2.58, 95% CI: 1.53, 4.37, P = 0.0004), while hyperlipidaemia (0.54, 95% CI: 0.35, 0.85; P = 0.008) and obesity (0.30, 95% CI: 0.15, 0.62; P = 0.001) were significantly decreased in AOSD patients. CONCLUSION: We characterized a first US-based AOSD cohort using a large national administrative claims database, and identified key complications, treatments and comorbidities.

Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula.

Neuronal nAChRs in the medial habenula (MHb) to the interpeduncular nucleus (IPN) pathway are key mediators of nicotine's aversive properties. In this paper, we report new details regarding nAChR anatomical localization and function in MHb and IPN. A new group of knock-in mice were created that each expresses a single nAChR subunit fused to GFP, allowing high-resolution mapping. We find that α3 and ß4 nAChR subunit levels are strong throughout the ventral MHb (MHbV). In contrast, α6, ß2, ß3, and α4 subunits are selectively found in some, but not all, areas of MHbV. All subunits were found in both ChAT-positive and ChAT-negative cells in MHbV. Next, we examined functional properties of neurons in the lateral and central part of MHbV (MHbVL and MHbVC) using brain slice patch-clamp recordings. MHbVL neurons were more excitable than MHbVC neurons, and they also responded more strongly to puffs of nicotine. In addition, we studied firing responses of MHbVL and MHbVC neurons in response to bath-applied nicotine. Cells in MHbVL, but not those in MHbVC, increased their firing substantially in response to 1 µm nicotine. Additionally, MHbVL neurons from mice that underwent withdrawal from chronic nicotine were less responsive to nicotine application compared with mice withdrawn from chronic saline. Last, we characterized rostral and dorsomedial IPN neurons that receive input from MHbVL axons. Together, our data provide new details regarding neurophysiology and nAChR localization and function in cells within the MHbV.

Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs.

α6ß2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6ß2* nAChRs (α6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6ß2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9'S NAc. Overall, these results show that enhanced α6ß2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels.

The Association of Gabapentin Initiation with Cognitive and Behavioral Changes in Older Adults with Cognitive Impairment: A Retrospective Cohort Study.

BACKGROUND: Although gabapentin has been increasingly prescribed to older adults, the relation between gabapentin initiation and longer-term neurocognitive changes is not well understood. Thus, this study aimed to examine the association of gabapentin initiation with cognitive and motor function decline in older adult participants with cognitive impairment. METHODS: A retrospective cohort study was conducted using the National Alzheimer's Coordinating Center Uniform Data Set (2005-March 2023). Participants with cognitive impairment at the visit of gabapentin initiation (i.e., index visit) were included. Using the incidence density sampling method, up to nine non-users were randomly selected for each initiator. Cognitive decline over 1 year was defined as any increase in Clinical Dementia Rating global score (CDR®GLOB) or a 1-point increase in CDR® sum of boxes (CDR®SB). Functional status decline over 1 year was defined as at least a 3-point increase in the Functional Activities Questionnaire (FAQ) sum or a 0.3-point increase of mean of FAQ. Motoric decline over 1 year was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, joint stabilized inverse probability of treatment weights and censoring weights were used. Analyses compared index with index + 1 and index + 2 visits. RESULTS: For the study of cognitive and functional status decline, we included 505 initiators (mean age [SD] 78.8 [7.4]; male = 45%) and 4545 non-users (79.2 [7.6]; 50.1%). For the study of motor decline, we included 353 initiators (78.3 [7.2]; 42.8%) and 3177 non-users (78.5 [7.4]; 48.1%). Gabapentin initiation was not statistically associated with decline on CDR®GLOB, CDR®SB, FAQ sum, or mean FAQ at the index + 1 or index + 2 visits. However, gabapentin initiation was significantly associated with increased odds of new falls at the index + 2 visit (odds ratio [95% confidence interval] 2.5 [1.3, 4.6]). CONCLUSIONS: Over 1 or 2 years of follow-up, gabapentin initiation was not associated with decline in cognitive or functional status but was associated with increased odds of falling among research participants with cognitive impairment.

The association of gabapentin initiation and neurocognitive changes in older adults with normal cognition.

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults. Methods: We conducted a retrospective cohort study using the National Alzheimer's Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits. Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]). Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.

Age- and sex-matched comparison of diet quality in patients with heart failure to similarly aged healthy older adults.

The aims of this study were to (1) compare diet quality between patients with heart failure (HF) and age- and sex-matched community-dwelling healthy older adults and (2) determine whether having HF was associated with a lower Healthy Eating Index-2015 (HEI-2015) score and risk of micronutrient deficiency. The HEI-2015 and macro- and micronutrient intakes of patients with HF were compared with healthy older adults (N 102; 55-92 years old; 53 % female). A paired t-test or Wilcoxon singed-rank test, McNemar's test, and conditional logistic regression were used to assess the association between diet quality and HF status. Median values for HEI-2015 and the number of micronutrient deficiency were used to dichotomise into groups in the conditional logistic regression. There was no significant between-group difference in the HEI-2015 total score (P 0⋅059), whereas the whole grain component was lower in patients with HF than in healthy older adults (3⋅1 ± 3⋅5 v. 4⋅5 ± 3⋅1, P 0⋅037; respectively). Total caloric intake was lower in patients with HF than in healthy older adults (1683 ± 595 v. 2104 ± 670 kcal; P < 0⋅001). Patients with HF had a higher average number of micronutrient deficiencies than healthy older adults (4[2, 6] v. 1[0, 4], respectively, P < 0⋅001). Patients with HF had four times higher odds of being in a high micronutrient deficiency group than healthy older adults, controlling for socio-demographics and body mass index (adjusted odds ratio [95 % confidence interval]: 4⋅04[1⋅06, 15⋅41]). Our findings demonstrate that diet quality measured by nutritional intake identifies patients with HF with lower caloric intake and higher micronutrient deficiencies compared with age- and sex-matched healthy older adults.

Predictors of chronic opioid therapy in Medicaid beneficiaries with HIV who initiated antiretroviral therapy.

The factors associated with chronic opioid therapy (COT) in patients with HIV is understudied. Using Medicaid data (2002-2009), this retrospective cohort study examines COT in beneficiaries with HIV who initiated standard combination anti-retroviral therapy (cART). We used generalized estimating equations on logistic regression models with backward selection to identify significant predictors of COT initiation. COT was initiated among 1014 out of 9615 beneficiaries with HIV (male: 10.4%; female: 10.7%). Those with older age, any malignancy, Hepatitis C infection, back pain, arthritis, neuropathy pain, substance use disorder, polypharmacy, (use of) benzodiazepines, gabapentinoids, antidepressants, and prior opioid therapies were positively associated with COT. In sex-stratified analyses, multiple predictors were shared between male and female beneficiaries; however, chronic obstructive pulmonary disease, liver disease, any malignancy, and antipsychotic therapy were unique to female beneficiaries. Comorbidities and polypharmacy were important predictors of COT in Medicaid beneficiaries with HIV who initiated cART.

Variation in Abuse-Deterrent Formulation Opioid Prescribing in California, Florida, and Kentucky in 2018.

PURPOSE: Abuse-deterrent formulation (ADF) opioid analgesics have been developed as a means to address prescription opioid abuse. ADF opioid use in clinical practice is not well described in the literature. This study characterizes ADF opioid prescribing patterns in 3 diverse states. METHODS: This study used data from prescription drug monitoring programs (PDMPs) in California, Florida, and Kentucky. The sample includes all ADF opioid prescriptions for patients ≥18 years old during the study period (CY 2018). Standardized prescribing rates were calculated by age, sex, and county rurality. The ADF opioid prescribing rate was calculated per 1,000 adult recipients of opioid analgesics. FINDINGS: The rate of ADF prescribing per 1,000 adult recipients of opioid analgesics was nearly twice as high in Florida (14.57; 95% CI: 14.44-14.69) than in California (8.30; 95% CI: 8.22-8.37) or Kentucky (8.20; 95% CI: 8.01-8.39). ADF prescribing rates were highest among adults ages 55-74 years and among males. ADF opioid prescribing in rural counties represented a greater proportion of total patients using opioid analgesics than in metro counties in California (RR 1.40; CI: 1.28-1.53). Opposite and less pronounced variation was observed in Kentucky (RR 0.93; 95% CI: 0.88-0.98), and a significant difference was not observed in Florida (RR 0.68; 95% CI: 0.38-1.19). CONCLUSIONS: There were significant differences in the ADF prescribing rates among the 3 states and in rural versus metro counties within 2 states. ADF opioid prescribing by age and sex showed similar trends within states. Further research is needed to elucidate contextual factors which may lead to prescribing variation.

Determinants of Sleep Medication Use among Participants in the National Alzheimer's Coordinating Center Uniform Data Set.

Sufficient sleep is critical for health in older adults, but prescription sleep aids are associated with numerous health risks (e.g., cognitive impairment and falls). We examine usage prevalence of two medication categories-sedative hypnotics (SH) and medications commonly used for insomnia (MCUFI)-among adults aged 45+ in the National Alzheimer's Coordinating Center data set. Analyzing the visits conducted between September 2005 and June 2018, we determine the factors associated with SH and MCUFI use, including sociodemographic, health, independence, and cognitive statuses. Usage rates were 9% for MCUFI (N = 3,279) and 4% for SH (N = 1,382). Multivariable logistic regression identified White race, higher education, younger age, depression, and sedative polypharmacy as factors associated with prescription sleep aid use. We conclude that sleep medication usage rates among older adults, higher likelihood of sedative medication polypharmacy, and higher likelihood of MCUFI use among adults with cognitive impairment are findings of concern and may warrant clinical intervention.

Patterns and predictors of chronic opioid use in older adults: A retrospective cohort study.

BACKGROUND: Given the controversy around the effectiveness of opioid treatment for chronic pain and the lack of detailed guidance for prescribing opioids in older adults, the objectives of this study were to estimate the trajectories and predictors of opioid use in older adults. METHODS: Data were extracted from the National Alzheimer's Coordinating Center (2005-2017). Group-based trajectory modeling was used to identify the patterns of opioid use (any or strong) among participants age 65+. We used multivariable logistic regression with backward selection to evaluate demographics and comorbidities as potential predictors of trajectory membership. RESULTS: Among 13,059 participants, four trajectories were identified for the use of both any opioids and strong opioids (minimal-users, incident chronic-users, discontinuing-users, and prevalent chronic-users). For any opioids, female sex (adjusted odds ratio = 1.23; 95% confidence interval = 1.03-1.46), black vs. white (1.47; 1.18-1.82), year of education (0.96; 0.94-0.99), type of residence (independent group vs. private: 1.77; 1.38-2.26, care facility vs. private: 1.89; 1.20-2.97), hypertension (1.44; 1.20-1.72), cardiovascular disease (1.30; 1.09-1.55), urinary incontinence (1.45; 1.19-1.78), dementia (0.73; 0.57-0.92), number of medications (1 to 4 vs. none: 0.48; 0.36-0.64, 5 or more vs. none: 0.67; 0.50-0.88), and antidepressant agent (1.38; 1.14-1.67) were associated with incident chronic-use vs. non-use. For strong opioids, female sex (1.27; 1.04-1.56), type of residence (independent group vs. private: 1.90; 1.43-2.53, care facility vs. private: 2.37; 1.44-3.90), current smoking (1.68; 1.09-2.60), hypertension (1.49; 1.21-1.83), urinary incontinence (1.45; 1.14-1.84), dementia (0.73; 0.55-0.97), number of medications (1 to 4 vs. none: 0.46; 0.32-0.65, 5 or more vs. none: 0.59; 0.42-0.83), and antidepressant agent (1.55; 1.24-1.93) were associated with incident chronic-use vs. non-use. CONCLUSION: Given that chronic opioid use was more prevalent in participants who were more vulnerable (i.e., older age, with multiple comorbidities, and polypharmacy), further studies should evaluate the safety and efficacy of using opioids in this population.