Assessing Substance Use Disorder Symptoms with a Checklist among Primary Care Patients with Opioid Use Disorder and/or Long-Term Opioid Treatment: An Observational Study.

BACKGROUND: Primary care (PC) offers an opportunity to treat opioid use disorders (OUD). The Substance Use Symptom Checklist ("Checklist") can assess DSM-5 substance use disorder (SUD) symptoms in PC. OBJECTIVE: To test the psychometric properties of the Checklist among PC patients with OUD or long-term opioid therapy (LTOT) in Kaiser Permanente Washington (KPWA). DESIGN: Observational study using item response theory (IRT) and differential item functioning (DIF) analyses of measurement consistency across age, sex, race and ethnicity, and receipt of treatment. PATIENTS: Electronic health records (EHR) data were extracted for all adult PC patients visiting KPWA 3/1/15-8/30/2020 who had ≥ 1 Checklist documented and indication of either (a) clinically-recognized OUD (i.e., documented OUD diagnosis and/or OUD medication treatment) or (b) LTOT in the year prior to the checklist. MAIN MEASURE: The Checklist includes 11 items reflecting DSM-5 criteria for SUD. We described the prevalence of 2 SUD symptoms reported on the Checklist (consistent with mild-severe DSM-5 SUD). Analyses were conducted in the overall sample and in two subsamples (clinically-recognized OUD and LTOT only). KEY RESULTS: Among 2007 eligible patients, 39.9% endorsed ≥ 2 SUD symptoms (74.3% in the clinically-recognized OUD subsample and 13.1% in LTOT subsample). IRT indicated that a unidimensional model for the 11 checklist items had excellent fit (comparative fit index = 0.998) with high item-level discrimination parameters for the overall sample and both subsamples. DIF across age, race and ethnicity, and treatment was observed for one item each, but had minimal impact on expected number of criteria (0-11) patients endorse. CONCLUSIONS: The Substance Use Symptom Checklist measured SUD symptoms consistent with DSM-5 conceptualization (scaled, unidimensional) in patients with clinically-recognized OUD and LTOT and had similar measurement properties across demographic subgroups. The Checklist may support symptom assessment in patients with OUD and diagnosis in patients with LTOT.

Integrating Buprenorphine for Opioid Use Disorder into Rural, Primary Care Settings.

BACKGROUND: Medications for opioid use disorder (MOUD) including buprenorphine are effective, but underutilized. Rural patients experience pronounced disparities in access. To reach rural patients, the US Department of Veterans Affairs (VA) has sought to expand buprenorphine prescribing beyond specialty settings and into primary care. OBJECTIVE: Although challenges remain, some rural VA health care systems have begun offering opioid use disorder (OUD) treatment with buprenorphine in primary care. We conducted interviews with clinicians, leaders, and staff within these systems to understand how this outcome had been achieved. DESIGN: Using administrative data from the VA Corporate Data Warehouse (CDW), we identified rural VA health care systems that had improved their rate of primary care-based buprenorphine prescribing over the period 2015-2020. We conducted qualitative interviews (n = 30) with staff involved in implementing or prescribing buprenorphine in these systems to understand the processes that had facilitated implementation. PARTICIPANTS: Clinicians, staff, and leaders embedded within rural VA health care systems located in the Northwest, West, Midwest (2), South, and Northeast. APPROACH: Qualitative interviews were analyzed using a mixed inductive/deductive approach. KEY RESULTS: Interviews revealed the processes through which buprenorphine was integrated into primary care, as well as processes insufficient to enact change. Implementation was often initially catalyzed through a targeted hire. Champions then engaged clinicians and leaders one-on-one to "pitch" the case, describe concordance between buprenorphine prescribing and existing goals, and delineate the supportive role that they could provide. Sites were prepared for implementation by developing new clinical teams and redesigning clinical processes. Each of these processes was made possible with the active, instrumental support of leadership. CONCLUSIONS: Results suggest that rural systems seeking to improve buprenorphine accessibility in primary care may need to alter primary care structures to accommodate buprenorphine prescribing, whether through new hires, team development, or clinical redesign.

Policies, adaptations, and ongoing challenges to naloxone, buprenorphine and nonprescription syringe access across four-states: Findings from an environmental scan and key informant interviews.

Background: As the US opioid-involved morbidity and mortality increase, uptake and implementation of evidence-based interventions remain key policy responses. Respond to Prevent was a multi-component, randomized trial implemented in four states and two large pharmacy chains with the aim of improving the pharmacy's capacity to provide naloxone, dispense buprenorphine, and sell nonprescription syringes (NPS). We sought to provide context and assess how policies and organizational practices affect communities and pharmacies across the study states. Methods: Using a multi-method approach we: 1) conducted an environmental scan of published literature and online materials spanning January 2015 to June 2021, 2) created timelines of key events pertaining to those policies and practices and 3) conducted semi-structured interviews with stakeholders (key informants) at the state and local levels (N=36) to provide further context for the policies and practices we discovered. Results: Key informants discussed state policies, pharmacy policies and local practices that facilitated access to naloxone, buprenorphine and NPSs. Interviewees from all states spoke about the impact of naloxone standing orders, active partnerships with community-based harm reduction organizations, and some federal and state policies like Medicaid coverage for naloxone and buprenorphine, and buprenorphine telehealth permissions as key facilitators. They also discussed patient stigma, access in rural settings, and high cost of medications as barriers. Conclusion: Findings underscore the important role harm reduction-related policies play in boosting and institutionalizing interventions in communities and pharmacies while also identifying structural barriers where more focused state and local attention is needed.

Preoperative Opioid Use Increases Postoperative Opioid Demand, but not Length of Stay after Spine Trauma Surgery.

BACKGROUND: Preoperative opioid use has been well-studied in elective spinal surgery and correlated with numerous postoperative complications including increases in immediate postoperative opioid demand (POD), continued opioid use postoperatively, prolonged length of stay (LOS), readmissions, and disability. There is a paucity of data available on the use of preoperative opioids in surgery for spine trauma, possibly because there are minimal options for opioid reduction prior to emergent spinal surgery. Nevertheless, patients with traumatic spinal injuries are at a high risk for adverse postoperative outcomes. This study investigated the effects of preoperative opioid use on POD and LOS in spine trauma patients. METHODS: 130 patients were grouped into two groups for primary comparison: Group 1 (Preoperative Opioid Use, N=16) and Group 2 (No Opioid Use, N=114). Two subgroups of Group 2 were used for secondary analysis against Group 1: Group 3 (No Substance Abuse, N=95) and Group 4 (Other Substance Abuse, N=19). Multivariable analysis was used to determine if there were significant differences in POD and LOS. RESULTS: Primary analysis demonstrated that preoperative opioid users required an estimated 97.5 mg/day more opioid medications compared to non-opioid users (p<0.001). Neither primary nor secondary analysis showed a difference in LOS in any of the comparisons. CONCLUSIONS: Preoperative opioid users had increased POD compared to non-opioid users and patients abusing other substances, but there was no difference in LOS. We theorize the lack of difference in LOS may be due to the enhanced perioperative recovery protocol used, which has been demonstrated to reduce LOS.

Cannabis use and acute postoperative pain outcomes in older adults: a propensity matched retrospective cohort study.

INTRODUCTION: Cannabis use is increasing among older adults, but its impact on postoperative pain outcomes remains unclear in this population. We examined the association between cannabis use and postoperative pain levels and opioid doses within 24 hours of surgery. METHODS: We conducted a propensity score-matched retrospective cohort study using electronic health records data of 22 476 older surgical patients with at least 24-hour hospital stays at University of Florida Health between 2018 and 2020. Of the original cohort, 2577 patients were eligible for propensity-score matching (1:3 cannabis user: non-user). Cannabis use status was determined via natural language processing of clinical notes within 60 days of surgery and structured data. The primary outcomes were average Defense and Veterans Pain Rating Scale (DVPRS) score and total oral morphine equivalents (OME) within 24 hours of surgery. RESULTS: 504 patients were included (126 cannabis users and 378 non-users). The median (IQR) age was 69 (65-72) years; 295 (58.53%) were male, and 442 (87.70%) were non-Hispanic white. Baseline characteristics were well balanced. Cannabis users had significantly higher average DVPRS scores (median (IQR): 4.68 (2.71-5.96) vs 3.88 (2.33, 5.17); difference=0.80; 95% confidence limit (CL), 0.19 to 1.36; p=0.01) and total OME (median (IQR): 42.50 (15.00-60.00) mg vs 30.00 (7.50-60.00) mg; difference=12.5 mg; 95% CL, 3.80 mg to 21.20 mg; p=0.02) than non-users within 24 hours of surgery. DISCUSSION: This study showed that cannabis use in older adults was associated with increased postoperative pain levels and opioid doses.

Pharmacologic Analgesia for Cesarean Section: An Update in 2024.

PURPOSE OF THE REVIEW: With the increasing prevalence of cesarean section globally, the importance of perioperative analgesia for cesarean section is becoming increasingly evident. This article provides an overview and update on the current status of cesarean section worldwide and associated analgesic regimens. RECENT FINDINGS: Some recent studies unveiled potential association of neuraxial analgesia might be associated with children's autism, pharmacologic analgesia in obstetric will potentially gain some more attention. Various commonly used techniques and medications for analgesia in cesarean section are highlighted. While neuraxial administration of opioid remains the most classic method, the use of multimodal analgesia, particularly integration of nonsteroidal anti-inflammatory drugs, acetaminophen, peripheral nerve blocks has provided additional and better options for patients who are not suitable for intrathecal and neuraxial techniques and those experiencing severe pain postoperatively. Optimal pain management is crucial for achieving better clinical outcomes and optimal recovery, and with the continuous development of medications, more and better pharmacologic regimen will be available in the future.

Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation.

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest.

Introduction: Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the µ-opioid receptor antagonists naloxone and nalmefene. Methods: This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment. Results: Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene. Conclusion: Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

Effect of repeated intraperitoneal injections of different concentrations of oxycodone on immune function in mice.

Background: The effect of oxycodone as an opioid receptor agonist on immune function is still controversial. In this study, we investigated the possible effects of oxycodone on immune function in mice and its possible mechanisms of action. Methods: By repeated intraperitoneal injections of 25 mg/kg morphine and 5 mg/kg, 20 mg/kg, and 60 mg/kg oxycodone, we assessed possible changes in the number of splenic lymphocytes and inflammatory cytokines in the serum of mice. CD4+ T cells and CD8+ T cells were sorted from the spleen to observe whether the expression levels of opioid receptors and downstream signals were altered. Results: Repeated administration of oxycodone at a dose above 20 mg/kg resulted in significant weight loss. Repeated administration of oxycodone exhibits significant dose-dependent reduction in CD4+ T cells, with little effect on CD8+ T cells and little effect on inflammatory cytokine levels. Low- and intermediate-dose oxycodone increased the mRNA expression level of MOR, KOR, and DOR to varying degrees. Moreover, oxycodone increases the mRNA expression levels of the TLR4 signaling pathway to varying degrees. Conclusion: Repeated intraperitoneal injection of oxycodone induces immunosuppression in mice.

Lateness of Acetaminophen and Non-steroidal Anti-inflammatory Drug Administrations in a Retrospective Cohort of Medication Administration Records Among Patients After Cesarean Delivery.

INTRODUCTION: In an earlier study of patients after cesarean delivery, the concurrent versus alternating administration of acetaminophen and non-steroidal anti-inflammatory drugs was associated with a substantial reduction in total postoperative opioid use. This likely pharmacodynamic effect may differ if the times when nurses administer acetaminophen and non-steroidal anti-inflammatory drugs often differ substantively from when they are due. We examined the "lateness" of analgesic dose administration times, the positive difference if administered late, and the negative value if early. METHODS: The retrospective cohort study used all 67,900 medication administration records for scheduled (i.e., not "as needed") acetaminophen, ibuprofen, and ketorolac among all 3,163 cesarean delivery cases at the University of Iowa between January 2021 and December 2023. Barcode scanning at the patient's bedside was used right before each medication administration. RESULTS: There were 95% of doses administered over a 4.8-hour window, from 108 minutes early (97.5% one-sided upper confidence limit 105 minutes early) to 181 minutes late (97.5% one-sided lower limit 179 minutes late). Fewer than half of doses (46%, P <0.0001) were administered ±30 minutes of the due time. The intraclass correlation coefficient was approximately 0.11, showing that there were small systematic differences among patients. There likewise were small to no systematic differences in lateness based on concurrent administrations of acetaminophen and ibuprofen or ketorolac, time of the day that medications were due, weekday, year, or number of medications to be administered among all such patients within 15 minutes. DISCUSSION: Other hospitals should check the lateness of medication administration when that would change their ability to perform or apply the results of analgesic clinical trials (e.g., simultaneous versus alternating administration).

Mobile addiction treatment and harm reduction services as tools to address health inequities: a community case study of the Brockton Neighborhood Health Center mobile unit.

Opioid overdose deaths continue to increase in the US. Recent data show disproportionately high and increasing overdose death rates among Black, Latine, and Indigenous individuals, and people experiencing homelessness. Medications for opioid use disorder (MOUD) can be lifesaving; however, only a fraction of eligible individuals receive them. Our goal was to describe our experience promoting equitable MOUD access using a mobile delivery model. We implemented a mobile MOUD unit aiming to improve equitable access in Brockton, a racially diverse, medium-sized city in Massachusetts. Brockton has a relatively high opioid overdose death rate with increasingly disproportionate death rates among Black residents. Brockton Neighborhood Health Center (BNHC), a community health center, provides brick-and-mortar MOUD access. Through the Communities That HEAL intervention as part of the HEALing Communities Study (HCS), Brockton convened a community coalition with the aim of selecting evidence-based practices to decrease overdose deaths. BNHC leadership and coalition members recognized that traditional brick-and-mortar treatment locations were inaccessible to marginalized populations, and that a mobile program could increase MOUD access. In September 2021, with support from the HCS coalition, BNHC launched its mobile initiative - Community Care-in-Reach® - to bring low-threshold buprenorphine, harm reduction, and preventive care to high-risk populations. During implementation, the team encountered several challenges including: securing local buy-in; navigating a complex licensure process; maintaining operations throughout the COVID-19 pandemic; and finally, planning for sustainability. In two years of operation, the mobile team cared for 297 unique patients during 1,286 total visits. More than one-third (36%) of patients received buprenorphine prescriptions. In contrast to BNHC's brick-and-mortar clinics, patients with OUD seen on the mobile unit were more representative of historically marginalized racial and ethnic groups, and people experiencing homelessness, evidencing improved, equitable addiction care access for these historically disadvantaged populations. Offering varied services on the mobile unit, such as wound care, syringe and safer smoking supplies, naloxone, and other basic medical care, was a key engagement strategy. This on-demand mobile model helped redress systemic disadvantages in access to addiction treatment and harm reduction services, reaching diverse individuals to offer lifesaving MOUD at a time of inequitable increases in overdose deaths.

The Effect of A2 Milk on Gastrointestinal Symptoms in Comparison to A1/A2 Milk: A Single-center, Randomized, Double-blind, Cross-over Study.

ß-Casein, a major protein in cow's milk, is divided into the A1 and A2 type variants. Digestion of A1 ß-casein yields the peptide ß-casomorphin-7 which could cause gastrointestinal (GI) discomfort but A2 milk containing only A2 ß-casein might be more beneficial than A1/A2 (regular) milk. The aim of this study was to evaluate the differences in GI discomfort after ingestion of A2 milk and A1/A2 milk. A randomized, double-blind, cross-over human trial was performed with 40 subjects who experienced GI discomfort following milk consumption. For each intervention period, either A2 milk first (A2→A1/A2) or A1/A2 milk was first consumed for 2 weeks (A1/A2→A2) following a 2-week washout period. GI symptom rating scale (GSRS) scores, questionnaire for digestive symptoms, and laboratory tests including fecal calprotectin were evaluated. For symptom analysis, generalized estimating equations gamma model was used. A2 milk increased bloating (P = 0.041) and loose stools (P = 0.026) compared to A1/A2 milk in GSRS. However, A2 milk caused less abdominal pain (P = 0.050), fecal urgency (P < 0.001) and borborygmus (P = 0.007) compared to A1/A2 milk in questionnaire for digestive symptoms. In addition, fecal calprotectin also decreased or less increased after consumption of A2 milk compared to A1/A2 milk (P = 0.030), and this change was more pronounced in males (P = 0.005) than in females. There were no significant adverse reactions during the trial. A2 milk alleviated digestive discomfort in Koreans following A2 milk consumption (ClinicalTrials.gov NCT06252636 and CRIS KCT0009301).

Predictors of retention in heroin-assisted treatment in Denmark 2010-2018 - A record-linkage study.

INTRODUCTION: While randomized-controlled trials have shown that heroin-assisted treatment (HAT) is superior to methadone maintenance alone in treatment of refractory clients, little is known about client factors associated with retention in HAT in routine care. METHODS: This retrospective cohort study assessed predictors of retention in first treatment episode among a consecutive cohort of clients admitted to HAT in Denmark from 2010 to 2018, who could be matched to the Danish population register and for whom a Short Form Health Survey (SF-36) was available at admission (N = 432). The study derived predictors from client self-reports at intake and administrative data available in national registers. Cox proportional hazards regression modelled retention in treatment. RESULTS: The one-year retention rate was 69.63 % (95 % CI 65.06 %-73.74 %), and the median time in treatment was 2.45 years (95 % CI, 1.83-3.12). Bivariate analyses showed that retention was lower for clients who had recent cocaine or benzodiazepine use and among those who had experienced an overdose in the year prior to enrollment in HAT. Age below 40, recent illegal activity, poorer emotional wellbeing, previous residential treatment experience, and previous intensive outpatient treatment were also predictors of dropout from HAT. CONCLUSIONS: This observational study found that retention in HAT in routine care was similar to rates observed in randomized-controlled trials conducted in other countries. The results suggest that addressing polysubstance use as part of the HAT program may promote long-term retention, as may directing resources to certain subgroups identified at intake, including clients under 40 years and those who report recent criminal activity, emotional problems, or overdoses. The findings that previous residential treatment and intensive outpatient treatment were associated with dropout were unexpected.

Recovery from opioid use on a neuropsychoanalytic service.

Background: Little is known about recovery from opioid use disorder (OUD) or outcomes of detoxification and drug-free treatment of chronic opioid therapy (COT). Harm reduction with medications for opioid use disorder (MOUD) is regarded as the only legitimate treatment. Methods: The Institutional Review Board (IRB) approved reporting deidentified outcomes. Patients seen over a 10-year period whose records suggested recovery were called and interviewed. Results: Overall, 69/86 (80%) confirmed that they had been sober for at least a year, including 41 patients with OUD (75%) and 28 COT patients (90%). 91% were drug-free, and 9% were on MOUD. 79% preferred a psychotherapy approach. 21% preferred MOUD. Coming for more treatment and abstinence from tobacco were significantly correlated with recovery. Conclusion: This is the first report that we are aware of regarding the frequency of recovery from OUD and COT. We have complicated the discussion about what is the best treatment for patients with OUD and patients on COT. Advising that maintenance is the only legitimate treatment for patients who suffer from OUD or who are on COT seems both premature and jeopardizes the ability of treaters to individualize treatment recommendations.

Acute Pain Management in a Multi-site Trauma Patient.

Pain management is often difficult in the setting of multi-site trauma such as that caused by motor vehicle accidents (MVA), which is especially compounded in the setting of polysubstance abuse. This often results in patients with poor pain tolerance requiring escalating doses of opioid therapy, which creates a vicious cycle. The use of peripheral nerve blocks (PNB) has been shown to decrease overall opioid consumption and can be used effectively to manage postoperative pain in this patient population. Our case report aims to highlight the importance of PNBs as part of a multimodal approach to pain management in patients with polytrauma in the setting of polysubstance abuse.

Self-help groups and opioid use disorder treatment: An investigation using a machine learning-assisted robust causal inference framework.

OBJECTIVES: This study investigates the impact of participation in self-help groups on treatment completion among individuals undergoing medication for opioid use disorder (MOUD) treatment. Given the suboptimal adherence and retention rates for MOUD, this research seeks to examine the association between treatment completion and patient-level factors. Specifically, we evaluated the causal relationship between self-help group participation and treatment completion for patients undergoing MOUD. METHODS: We used the Substance Abuse and Mental Health Services Administration's (SAMHSA) Treatment Episode Data Set: Discharges (TEDS-D) from 2015 to 2019. The data are filtered by the patient's opioid use history, demographics, treatment modality, and other relevant information. In this observational study, machine learning models (Lasso Regression, Decision Trees, Random Forest, and XGBoost) were developed to predict treatment completion. Outcome Adaptive Elastic Net (OAENet) was used to select confounders and outcome predictors, and the robust McNemars test was used to evaluate the causal relationship between self-help group participation and MOUD treatment completion. RESULTS: The machine-learning models showed a strong association between participation in self-help groups and treatment completion. Our causal analysis demonstrated an average treatment effect on treated (ATT) of 0.260 and a p-value < 0.0001 for the robust McNemars test. CONCLUSIONS: Our study demonstrates the importance of participation in self-help groups for MOUD treatment recipients. We found that participation in MOUD along with self-help groups caused higher chances of treatment completion than MOUD alone. This suggests that policymakers should consider further integrating self-help groups into the treatment for OUD to improve the adherence and completion rate.

Trends in recurrent overdose and treatment initiation following emergency department visits for opioid overdose between 2016 and 2021.

BACKGROUND: Overdose remains a pressing public health concern in the United States, particularly with the emergence of fentanyl and other potent synthetic opioids in the drug supply. We evaluated trends in recurrent overdose and opioid use disorder (OUD) treatment initiation following emergency department (ED) visits for opioid overdose to inform response efforts. METHODS: This retrospective cohort study used electronic health record and statewide administrative data from Rhode Island residents who visited EDs for opioid overdose between July 1, 2016, and June 30, 2021, a period with fentanyl predominance in the local drug supply. The primary outcome was recurrent overdose in the 365 days following the initial ED visit. OUD treatment initiation within 180 days following the initial ED visit was considered as a secondary outcome. Trends in study outcomes were summarized by year of the initial ED visit. RESULTS: Among 1745 patients attending EDs for opioid overdose, 20 % (n=352) experienced a recurrent overdose within 365 days, and this percentage was similar by year (p=0.12). Among patients who experienced any recurrent overdose, the median time to first recurrent overdose was 88 days (interquartile range=23-208), with 85 % (n=299/352) being non-fatal. Among patients not engaged in OUD treatment at their initial ED visit, 33 % (n=448/1370) initiated treatment within 180 days; this was similar by year (p=0.98). CONCLUSIONS: Following ED visits for opioid overdose in Rhode Island from 2016-2021, the one-year risk of recurrent overdose and six-month treatment initiation rate remained stable over time. Innovative prevention strategies and improved treatment access are needed.

Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists.

Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing -S- → -CH2- replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure-activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1.

Aberrant type 2 dopamine receptor availability in violent offenders with psychopathy.

Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n=11) and healthy matched controls (n=17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.