Identifying bright spot communities: Socioecological, workforce, and healthcare delivery factors influencing opioid mortality.

Context: There were 50,000 U.S. opioid overdose deaths in 2019. Millions suffer from opioid addiction. Identifying protective factors for low community opioid mortality may have important implications for addressing the opioid epidemic. This study was funded through the Virginia (VA) Department of Medical Assistance Services (DMAS) through a SUPPORT Act Grant. Objective: To identify "Bright Spot" communities in Virginia with protective factors associated with reduced opioid mortality and morbidity. Study Design: Ecologic study. Dataset: Virginia All Payer Claims Database (APCD), Virginia Department of Health (VDH) statewide medical examiner registry, and American Community Survey (ACS). Time Period: 2016-2019; 2019 data cited here. Population Studied: APCD includes VA residents with medical claims through commercial, Medicaid, and Medicare coverage. VDH data includes fatal drug overdoses. ACS surveys all VA residents. Outcome Measures: Primary outcome: fatal opioid overdoses. Secondary outcomes: emergency room visits for overdoses and opioid-related diagnoses, outpatient diagnoses for opioid-related disorder, prescription rate for opioids, and prescription rate for buprenorphine. Results: Opioid mortality was associated with higher rates of community poverty (r=.38, p<.0001) and disability (r=.52, r<.0001). Opioid mortality was associated with inequality, with higher Gini index associated with higher opioid mortality (r=.23, p<.0001). A higher percentage of black residents was associated with increased fatal opioid overdoses (r=.37, p<.0001) and ED visits for overdoses (r=.30, p<.0001). A higher percentage of white residents correlated with increased outpatient visits for opioid use disorder (r=.24, p<.0001) and higher rates of buprenorphine (r=.34, p<.0001) and opioid prescriptions (r=.31, p <.0001). Conclusions: These findings suggest significant racial disparities in opioid outcomes. Communities with a higher percentage of black residents are more likely to have higher opioid mortality and a lower rate of outpatient treatment. This association may be affected by the time period used in the analysis (2015-2019), as nationally there has been an increasing rate of synthetic opioid deaths in Black communities. These measures have been incorporated into a multivariate analysis to identify Bright Spot communities, which will be discussed during the presentation.

Altered effective connectivity of the reward network during an incentive-processing task in adults with alcohol use disorder.

BACKGROUND: Abnormalities of reward sensitivity and impulsivity are known to be correlated with each other and alcohol use disorder (AUD) risk, but the underlying aberrant neural circuitry involved is not clearly defined. We sought to extend the current knowledge of AUD pathophysiology by studying incentive processing in persons with AUD using functional neuroimaging data. METHODS: We utilized functional MRI data from the Human Connectome Project Database obtained during performance of a number-guessing incentive-processing task with win, loss, and neutral feedback conditions in 78 participants with either DSM-IV alcohol abuse or dependence (combined as the AUD group) and 78 age- and sex-matched control (CON) participants. Within a network consisting of anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), insula, ventral striatum, and dorsal striatum (DS) in the right hemisphere, we performed dynamic causal modeling analysis to test group-level differences (AUD vs. CON) in effective directional connectivity (EC) as modulated by "win" and "loss" conditions. We used linear regression analyses to characterize the relations between each EC outcome and measures of cumulative alcohol exposure and impulsivity. RESULTS: During wins, AUD participants had lower ECs from ACC to the other four nodes, greater ECs from insula to the other four nodes, greater ECs from DLPFC to the other four nodes, and greater DS to DS self-connection EC than CON participants. In the total sample, EC from the insula to the DLPFC (insula â†’ DLPFC) during wins was positively correlated with both impulsivity (as measured by the delay-discounting task) and cumulative alcohol exposure. The DS to DS self-connection EC during wins was positively correlated with impulsivity. Many of the altered ECs from the ACC and insula to other nodes were correlated with cumulative alcohol exposure. CONCLUSIONS: Individuals with AUD have disrupted EC in both instrumentally driven and automatized corticostriatal reward circuits during non-alcohol reward feedback. These results point to disrupted corticostriatal EC in both "top-down" and "bottom-up" pathways among individuals with AUD.

Noninvasive Hemodynamic Monitoring of Cocaine-Induced Changes in Cardiac Output and Systemic Vascular Resistance in Subjects With Chronic Cocaine Use Disorder.

BACKGROUND: Cocaine use disorder (CUD) is a common problem in the United States and worldwide. The mechanisms by which cocaine induces acute cardiovascular toxicity are various. When systemically absorbed through inhaled or intravenous routes, cocaine induces an acute rise in the heart rate (HR) and blood pressure (BP) leading to a significant increase in the cardiac output (CO) and myocardial oxygen demand. Subjects with chronic CUD represent a special population that has experienced long-term cocaine exposure, often without showing signs of cardiovascular disease. We herein present prospectively collected data on the acute hemodynamic effects of intravenous cocaine in a cohort of nontreatment-seeking individuals with CUD without cardiovascular disease. METHODS AND RESULTS: Baseline physiologic data were collected while participants underwent infusion of escalating doses of cocaine (10, 20, and 40 mg administered over 2 minutes) at baseline and after receiving single-blind placebo treatment. Continuous noninvasive hemodynamic monitoring was performed throughout the infusion sessions using the ccNexfin finger cuffs (Edwards Lifesciences Corp, Irvine, CA). The recorded arterial BP tracings allowed for the measurement of beat-to-beat changes in HR, BP, stroke volume, CO, and systemic vascular resistance (SVR). None of the subjects experienced a treatment-related serious adverse event. Cocaine produced significant dose-dependent increases in median HR, BP, CO, and +dP/dt (a measure of cardiac contractility) and a significant dose-dependent reduction in median SVR. CONCLUSIONS: Intravenous cocaine in a cohort of otherwise healthy subjects with CUD produced dose-dependent increases in CO, largely explained by an increase in HR, accompanied by a dose-dependent decrease in SVR.

Prevalence of traumatic brain injury in cocaine-dependent research volunteers.

BACKGROUND: There is a high prevalence of traumatic brain injury (TBI) among those with substance dependence. However, TBI often remains undiagnosed in these individuals, due to lack of routine screening in substance use treatment settings or due to overlap in some of the cognitive sequelae (eg impulsivity, disinhibition) of TBI and cocaine dependence. METHODS: The prevalence of self-reported mild to moderate TBI in a group of cocaine-dependent (n = 95) and a group of healthy volunteers (n = 75) enrolled at the same facility was assessed. Additionally, the relationship between TBI and clinically relevant correlates, including impulsivity, cocaine use history, and treatment outcome in the cocaine-dependent group was also examined. RESULTS: A higher proportion of individuals with cocaine dependence (29.5%) reported having suffered a TBI in their lifetime compared to controls (8%) on a Closed Head Injury scale. Among cocaine users, the average age of sustaining TBI was significantly lower than the age of initiating cocaine use. Presence of TBI was not associated with higher impulsivity on the Barratt Impulsiveness Scale-11 or self-reported years of cocaine use. No differences were noted on treatment outcome for cocaine dependence as measured by treatment effectiveness scores (TES) between cocaine users with TBI and their non-TBI counterparts. CONCLUSIONS: These results are the first to highlight the high prevalence of TBI among individuals with cocaine dependence. This study underscores the possible role of TBI history as a risk factor for onset of cocaine use, however, more research is needed to determine the impact of co-morbid TBI as a complicating factor in the substance abuse treatment setting.

The influence of dopamine ß-hydroxylase gene polymorphism rs1611115 on levodopa/carbidopa treatment for cocaine dependence: a preliminary study.

Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy. Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine ß-hydroxylase (DßH). Seventy-one cocaine-dependent patients who participated in a 12-week randomized double-blind placebo-controlled trial of levodopa/carbidopa were genotyped for the DßH gene (DBH) polymorphism rs1611115. Our results showed that for patients with the low DßH activity genotypes (CT/TT) who received levodopa, the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes (P=0.004). Individuals with the normal DßH activity genotype (CC) showed no differential response to levodopa. These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism.

Development and clinical feasibility study of a brief version of an addiction-focused phenotyping battery in females receiving buprenorphine for opioid use disorder.

INTRODUCTION: We aimed to streamline the NIDA Phenotyping Assessment Battery (PhAB), a package of self-report scales and neurobehavioral tasks used in substance use disorder (SUD) clinical trials, for clinical administration ease. Tailoring the PhAB to shorten administration time for a treatment setting is critical to expanding its acceptability in SUD clinical trials. This study's primary objectives were to develop a brief version of PhAB (PhAB-B) and assess its operational feasibility and acceptability in a female clinical treatment sample. METHODS: Assessments of the original PhAB were evaluated along several criteria to identify a subset for the PhAB-B. Non-pregnant females (N=55) between ages 18-65, stabilized on buprenorphine for opioid use disorder (OUD) at an outpatient addiction clinic, completed this abbreviated battery remotely or after a provider visit in clinic. Participant satisfaction questions were administered. REDCap recorded the time to complete PhAB-B measures. RESULTS: The PhAB-B included 11 measures that probed reward, cognition, negative emotionality, interoception, metacognition, and sleep. Participants who completed the PhAB-B (N =55) were 36.1 ± 8.9 years of age, White (54.5%), Black (34.5%), and non-Latinx (96.0%). Most participants completed the PhAB-B remotely (n = 42, 76.4%). Some participants completed it in-person (n = 13, 23.6%). PhAB-B mean completion time was 23.0 ± 12.0 min. Participant experiences were positive, and 96% of whom reported that they would participate in the study again. CONCLUSION: Our findings support the clinical feasibility and acceptability of the PhAB-B among a female opioid use disorder outpatient addiction treatment sample. Future studies should assess the PhAB-B psychometric properties among broader treatment samples.

Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats.

Alterations in the balance of functional activity within the serotonin [5-hydroxytryptamine (5-HT)] system are hypothesized to underlie impulse control. Cocaine-dependent subjects consistently show greater impulsivity relative to nondrug using control subjects. Preclinical studies suggest that the 5-HT(2A) receptor (5-HT(2A)R) contributes to the regulation of impulsive behavior and also mediates some of the behavioral effects of cocaine. We hypothesized that the selective 5-HT(2A)R antagonist M100907 would reduce inherent levels of impulsivity and attenuate impulsive responding induced by cocaine in two animal models of impulsivity, the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. M100907 reduced rates of responding in the DRL task and premature responding in the 1-CSRT task. Conversely, cocaine disrupted rates of responding in the DRL task and increased premature responding in the 1-CSRT task. M100907 attenuated cocaine-induced increases in specific markers of behavioral disinhibition in the DRL and 1-CSRT tasks. These results suggest that the 5-HT(2A)R regulates inherent impulsivity, and that blockade of the 5-HT(2A)R alleviates specific aspects of elevated levels of impulsivity induced by cocaine exposure. These data point to the 5-HT(2A)R as an important regulatory substrate in impulse control.

The Use of Once-monthly Injectable Buprenorphine for the Treatment of Opioid Use Disorder in Postpartum Women: A Case Series.

OBJECTIVES: For women with opioid use disorder (OUD), the postpartum period is an especially vulnerable period. Buprenorphine (BUP) improves OUD outcomes during this timeframe. Once-monthly injectable BUP (XRI-BUP) is a newer formulation for which evidence of use in postpartum women is extremely limited. We present a case series of 9 women who transitioned from sublingual (SL-BUP) to XRI-BUP in their first year postpartum. METHODS: We conducted a retrospective chart review of our institution's medical record for patients who received at least one administration of XRI-BUP in their first year postpartum (January 2017-March 2020). Data were collected from baseline through mean follow-up of 281.4 days (range 235-417) for participant outcomes. RESULTS: The most common indications for initiating XRI-BUP were participant preference (n = 9) followed by challenges taking SL-BUP (n = 6). Four of the 9 participants transitioned back from XRI- to SL-BUP during the study timeframe, for reasons including incarceration and undesired side effects. Preliminary treatment outcomes demonstrated that participants remained on SL- (n = 4) or XRI-BUP (n = 5) through follow-up. The 5 participants who remained on XRI-BUP had consistent negative urine drug tests for nonprescribed opioids during the study period. CONCLUSIONS: To our knowledge, this is the first study that reviews the feasibility of using XRI-BUP in postpartum women. Our results suggest that XRI-BUP is a viable treatment option, which should be further investigated in future studies of postpartum women with OUD.

Sex-specific risk profiles for substance use among college students.

INTRODUCTION: Growing evidence indicates sex and gender differences exist in substance use. Framed by a lifecourse perspective, we explored prospectively by sex the effects of distal and proximal factors on the initiation of drug use in college. METHODS: College students without prior drug use (n = 5,120 females; n = 2,951 males) were followed longitudinally across 4 years. Analyses were estimated as a multigroup survival analysis separately by sex within a latent variable SEM framework with illicit drug use (6 or more times in past year) as the latent factor. RESULTS: More males initiated drug use (8.5%) than females (6.4%, χ2 (1) = 10.351, p = .001), but less so for Black males (AOR 0.33, 95% CI [0.18, 0.60]) and females (0.35 [0.23, 0.54]). Students initiating drug use more likely included students smoking cigarettes at baseline (males 1.40 [1.23, 1.59]; females 1.43 [1.24, 1.64]), using alcohol (males 1.04 [1.02, 1.06]; females 1.04 [1.02, 1.06]), or having cannabis using peers (males 1.79 [1.52, 2.11]; females 1.70 [1.49, 1.93]). Impulsivity domain associations differed by sex [negative urgency: females (1.23 [1.02, 1.49) and sensation seeking: males (1.33 [1.01, 1.75])]. History of unwanted/uncomfortable sexual experience predicted drug use for males (1.60 [1.09, 2.35]) and females (1.95 [1.45, 2.62]) but physical assault only for females (1.45 [1.08, 1.94]). Mood symptoms predicted drug use only for males [depression (0.73 [0.56, 0.95]); anxiety (1.40 [1.04, 1.89])]. CONCLUSIONS: Risk factors for initiating drug use during college differ by sex. As substance use during early age predisposes one for addiction, sex- and gender-informed interventions for young adults are needed.

Dynamic Causal Modeling Self-Connectivity Findings in the Functional Magnetic Resonance Imaging Neuropsychiatric Literature.

Dynamic causal modeling (DCM) is a method for analyzing functional magnetic resonance imaging (fMRI) and other functional neuroimaging data that provides information about directionality of connectivity between brain regions. A review of the neuropsychiatric fMRI DCM literature suggests that there may be a historical trend to under-report self-connectivity (within brain regions) compared to between brain region connectivity findings. These findings are an integral part of the neurologic model represented by DCM and serve an important neurobiological function in regulating excitatory and inhibitory activity between regions. We reviewed the literature on the topic as well as the past 13 years of available neuropsychiatric DCM literature to find an increasing (but still, perhaps, and inadequate) trend in reporting these results. The focus of this review is fMRI as the majority of published DCM studies utilized fMRI and the interpretation of the self-connectivity findings may vary across imaging methodologies. About 25% of articles published between 2007 and 2019 made any mention of self-connectivity findings. We recommend increased attention toward the inclusion and interpretation of self-connectivity findings in DCM analyses in the neuropsychiatric literature, particularly in forthcoming effective connectivity studies of substance use disorders.

Recent research on impulsivity in individuals with drug use and mental health disorders: implications for alcoholism.

Alcohol misuse and dependence, and many of its accompanying psychological problems, are associated with heightened levels of impulsivity that both accelerate the development of clinically significant illness and complicate clinical outcome. This article reviews recent developments in our understanding of impulsivity as they relate to brain circuitry that might underlie these comorbid factors, focusing upon the clinical features of substance use (and dependence), bipolar disorder, and pathological gambling. Individuals who are affected by these disorders exhibit problems in several domains of impulsive behavior including deficient response or "motor" control, and the tolerance of prolonged delays prior to larger rewards at the expense of smaller rewards ("delay-discounting"). These populations, like alcoholic dependents, also exhibit impairments in risky decision-making that may reflect dysfunction of monoamine and catecholamine pathways. However, several areas of uncertainty exist including the specificity of impairments across disorders and the relationship between impulse control problems and altered evaluation of reward outcomes underlying observed impairments in action selection.

Brain Integrity Changes Underlying Cognitive and Functional Recovery Postliver Transplant Continue to Evolve Over 1 Year.

BACKGROUND: There is evidence of brain recovery on brain magnetic resonance imaging (MRI) early postliver transplant (LT), but the longer-term impact is unclear. The aim of this study was to determine the change in brain MRI parameters, cognition, and health-related quality of life (HRQOL) between 6 and 12 months post-LT. METHODS: Listed cirrhotics underwent cognitive, HRQOL and brain MRI pre-LT, 6 months (post-LT1), and 1-year (post-LT2) post-LT. Assessment of MRI changes between visits was performed for ammonia-associated metabolite changes using magnetic resonance spectroscopy, white matter changes using tract-based spatial statistics analysis on diffusion tensor imaging data and grey matter changes using voxel-based morphometry analysis on 3D high resolution T1-weighted images. RESULTS: Forty-five patients were included, of which 23 were tested at all visits. Cognitive and HRQOL scores improved between all visits compared with pre-LT values. This trend continued on magnetic resonance spectroscopy with reduced glutamine + glutamate and higher myoinositol, choline between pre-LT/post-LT1 but lower degrees of improvement between post-LT1/post-LT2. On diffusion tensor imaging, mean diffusivity, linear diffusivity and mode of anisotropy continued to increase in the posterior internal capsule at both post-LT visits. On voxel-based morphometry, a continued increase was seen in basal ganglia grey matter between both post-LT visits was seen. CONCLUSIONS: HRQOL and cognition continue to improve compared with pre-LT values up to 1 year post-LT, although the rate of improvement slows down after 6 months. Grey matter increase is steady over time at 1 year although changes in ammonia-related metabolites and white matter integrity improve at a slower pace at 1 year post-LT.

Impulsivity and BOLD fMRI activation in MDMA users and healthy control subjects.

The correlation between scores on the Barratt Impulsiveness Scale (BIS) and activation measured by functional magnetic resonance imaging in a dorsolateral prefrontal cortical (DLPFC) activating task was examined in 15 MDMA-using subjects and 19 controls. A significant correlation between BIS scores and DLPFC activation was found, supporting a role for the DLPFC in BIS-measured impulsivity.

Utility of Machine-Learning Approaches to Identify Behavioral Markers for Substance Use Disorders: Impulsivity Dimensions as Predictors of Current Cocaine Dependence.

BACKGROUND: Identifying objective and accurate markers of cocaine dependence (CD) can innovate its prevention and treatment. Existing evidence suggests that CD is characterized by a wide range of cognitive deficits, most notably by increased impulsivity. Impulsivity is multidimensional and it is unclear which of its various dimensions would have the highest predictive utility for CD. The machine-learning approach is highly promising for discovering predictive markers of disease. Here, we used machine learning to identify multivariate predictive patterns of impulsivity phenotypes that can accurately classify individuals with CD. METHODS: Current cocaine-dependent users (N = 31) and healthy controls (N = 23) completed the self-report Barratt Impulsiveness Scale-11 and five neurocognitive tasks indexing different dimensions of impulsivity: (1) Immediate Memory Task (IMT), (2) Stop-Signal Task, (3) Delay-Discounting Task (DDT), (4) Iowa Gambling Task (IGT), and (5) Probabilistic Reversal-Learning task. We applied a machine-learning algorithm to all impulsivity measures. RESULTS: Machine learning accurately classified individuals with CD and predictions were generalizable to new samples (area under the curve of the receiver-operating characteristic curve was 0.912 in the test set). CD membership was predicted by higher scores on motor and non-planning trait impulsivity, poor response inhibition, and discriminability on the IMT, higher delay discounting on the DDT, and poor decision making on the IGT. CONCLUSION: Our results suggest that multivariate behavioral impulsivity phenotypes can predict CD with high degree of accuracy, which can potentially be used to assess individuals' vulnerability to CD in clinical settings.

Reduced anterior corpus callosum white matter integrity is related to increased impulsivity and reduced discriminability in cocaine-dependent subjects: diffusion tensor imaging.

Brain imaging studies find evidence of prefrontal cortical dysfunction in cocaine-dependent subjects. Similarly, cocaine-dependent subjects have problems with behaviors related to executive function and impulsivity. Since prefrontal cortical axonal tracts cross between hemispheres in the corpus callosum, it is possible that white matter integrity in the corpus callosum could also be diminished in cocaine-dependent subjects. The purpose of this study was to compare corpus callosum white matter integrity as measured by the fractional anisotropy (FA) on diffusion tensor imaging (DTI) between 18 cocaine-dependent subjects and 18 healthy controls. The Barratt Impulsiveness Scale (BIS-11) and a continuous performance test: the Immediate and Delayed Memory Task (IMT/DMT) were also collected. Results of the DTI showed significantly reduced FA in the genu and rostral body of the anterior corpus callosum in cocaine-dependent subjects compared to controls. Cocaine-dependent subjects also had significantly higher BIS-11 scores, greater impulsive (commission) errors, and reduced ability to discriminate target from catch stimuli (discriminability) on the IMT/DMT. Within cocaine dependent subjects there was a significant negative correlation between FA in the anterior corpus callosum and behavioral laboratory measured impulsivity, and there was a positive correlation between FA and discriminability. The finding that reduced integrity of anterior corpus callosum white matter in cocaine users is related to impaired impulse control and reduced ability to discriminate between target and catch stimuli is consistent with prior theories regarding frontal cortical involvement in impaired inhibitory control in cocaine-dependent subjects.

Diffusion tensor imaging and decision making in cocaine dependence.

BACKGROUND: Chronic stimulant abuse is associated with both impairment in decision making and structural abnormalities in brain gray and white matter. Recent data suggest these structural abnormalities may be related to functional impairment in important behavioral processes. METHODOLOGY/PRINCIPAL FINDINGS: In 15 cocaine-dependent and 18 control subjects, we examined relationships between decision-making performance on the Iowa Gambling Task (IGT) and white matter integrity as measured by diffusion tensor imaging (DTI). Whole brain voxelwise analyses showed that, relative to controls, the cocaine group had lower fractional anisotropy (FA) and higher mean of the second and third eigenvalues (lambda perpendicular) in frontal and parietal white matter regions and the corpus callosum. Cocaine subjects showed worse performance on the IGT, notably over the last 40 trials. Importantly, FA and lambda perpendicular values in these regions showed a significant relationship with IGT performance on the last 40 trials. CONCLUSIONS: Compromised white matter integrity in cocaine dependence may be related to functional impairments in decision making.

Initial platelet serotonin (5-HT) transport kinetics predict nortriptyline treatment outcome.

According to the hypothesis of initial conditions, drug response may be determined by different initial states of neurotransmitter protein recognition systems. Platelet serotonin (5-HT) transport kinetics were studied as initial-conditions predictors of antidepressant response in 24 depressed patients before and after 3 weeks of treatment with nortriptyline (75 mg). The initial affinity of the 5-HT transporter (5-HTT) correctly predicted 71% of the outcome. The pretreatment affinity constant ( Km) correlated (r = 0.61; p < 0.002) with that measured after 3 weeks of treatment (Kapp). Responding patients had a significantly higher initial Km before treatment and a significantly higher Kapp after treatment. Nonresponders had an initial Km significantly lower than that of 24 controls. Nortriptyline plasma levels were not statistically different between response groups. These results are consistent with two previously published observations, which indicate that the initial affinity of the 5-HTT predicted response to fluvoxamine or fluoxetine in the same way. Insofar as all three drugs increase the apparent affinity of the 5-HTT, it appears that a better response is related to those cases where the initial affinity is already higher before treatment.