Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism.

Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions.

Case report: Dezocine's rapid and sustained antidepressant effects.

Anhedonia and motivational impairments are cardinal features of depression, against which conventional antidepressants demonstrate limited efficacy. Preclinical investigations and extant clinical trial data substantiate the promise of opioid receptor modulators in addressing anhedonia, depression, and anxiety. While synthetic opioid agents like dezocine are conventionally employed for analgesia, their distinctive pharmacological profile has engendered interest in their potential antidepressant properties and translational applications. Herein, we present a case in which persistent bupropion treatment was ineffective. However, the incidental administration of a single low-dose intravenous injection of dezocine resulted in a rapid and sustained amelioration of depressive symptoms, particularly anhedonia and motivational deficits. Our findings posit a potentially novel role for the "legacy drug" dezocine.

Effect of A118G (rs1799971) single-nucleotide polymorphism of the µ-opioid receptor OPRM1 gene on intraoperative remifentanil requirements in Japanese women undergoing laparoscopic gynecological surgery.

AIM: Abundant data are available on the effect of the A118G (rs1799971) single-nucleotide polymorphism (SNP) of the µ-opioid receptor OPRM1 gene on morphine and fentanyl requirements for pain control. However, data on the effect of this SNP on intraoperative remifentanil requirements remain limited. We investigated the effect of this SNP on intraoperative remifentanil requirements. METHODS: We investigated 333 Japanese women, aged 21-69 years, who underwent laparoscopic gynecological surgery for benign gynecological disease under total intravenous anesthesia at Juntendo University Hospital. Average infusion rates of propofol and remifentanil during anesthesia and the average bispectral index (BIS) during surgery were recorded. Associations among genotypes of the A118G and phenotypes were examined with the Mann-Whitney U test. RESULTS: The average propofol infusion rate was not different between patients with different genotypes. The average remifentanil infusion rate was significantly higher in patients with the AG or GG genotype than the AA genotype (p = 0.028). The average intraoperative BIS was significantly higher in patients with the GG genotype than the AA or AG genotype (p = 0.039). CONCLUSIONS: The G allele of the A118G SNP was associated with higher intraoperative remifentanil requirements and higher intraoperative BIS values but was not associated with propofol requirements. Given that remifentanil and propofol act synergistically on the BIS, these results suggest that the G allele of the A118G SNP is associated with lower effects of remifentanil in achieving adequate intraoperative analgesia and in potentiating the sedative effect of propofol on the BIS.

Fluorofentanyl and Novel Synthetic Opioids in Accidental Overdose Deaths.

One of the quickest-growing subclasses of novel psychoactive substances is novel synthetic opioids (NSO), which are categorized as fentanyl analogs (fentalogs) or non-fentanyl opioids that bind to the mu-opioid receptor. Increased detections of NSO have been observed in the United States. However, limited information on their prevalence outside of the East Coast is available. This study details the prevalence of NSO, specifically fluorofentanyl, in the biological and drug paraphernalia specimens of accidental overdose deaths in San Francisco in 2022. A recently developed and validated LC-MS-MS method was utilized for the analysis of over 250 NSO. Out of the 649 accidental overdose deaths in 2022, 617 cases were available for blood analysis, with at least one NSO detected in 48 cases (7.8%). Fentalogs were detected in all 48 cases, with fluorofentanyl being detected in 40 cases. In postmortem femoral blood, estimated concentrations of fluorofentanyl ranged from 0.1 to 8.9 ng/mL, and 0.05 to 85 ng/mL in urine. Polysubstance use with NSO was seen with fentanyl (89.6%), methamphetamine (70.8%), cocaine (33.3%), and heroin (18.8%). NSO, mainly, fluorofentanyl were observed in matched drug paraphernalia. This report documents the migration of fluorofentanyl to the West Coast, specifically California.

Study Protocol for the Opioid and Pain Treatment in Indigenous Communities Trial: A Systems Level Intervention for Enhanced Screening and Brief Intervention and Referral for Co-Occurring Chronic Pain and Opioid Use Disorder.

American Indian/Alaska Native (AI/AN) individuals have the highest rates of opioid overdose mortality and chronic pain (CP) compared to other racial/ethnic groups in the United States. These individuals also report higher rates of pain anxiety and pain catastrophizing, which are both associated with poorer outcomes and risk for opioid misuse (OM) and opioid use disorder (OUD) among individuals with CP. Yet, no prior studies have examined rates of comorbid pain and OUD among AI/AN adults. This commentary describes an implementation research partnership of 3 AI/AN-serving clinics and a university team that utilizes an implementation hybrid type III design to examine the impact of implementation strategies on adoption and sustainability of evidence-based screening and brief intervention for CP and OM/OUD among AI/AN clients. As part of our community-engaged approach, we embrace both AI/AN models and Western models, and a collaborative board of 10 individuals guided the research throughout. We hypothesize that our culturally centered approach will increase rates of screening and brief intervention and improve identification of and outcomes among AI/AN clients with CP and OUD who receive treatment at participating sites. Each site convenes a workgroup to evaluate and set goals to culturally center screening and brief interventions for CP and OM/OUD. Data collected include deidentified electronic health records to track screening and brief interventions and rates of CP and OUD; provider and staff surveys beginning prior to implementation and every 6 months for 2 years; and a subset of clients will be recruited (N = 225) and assessed at baseline, 6, and 12 months to examine biopsychosocial and spiritual factors and their experiences with culturally centered screening and brief intervention. Cultural adaptations to the measures and screening and brief intervention as well as barriers and facilitators will be addressed. Recommendations for successful Tribal health clinic-university partnerships are offered.

Development of a Patient and Clinician Informed Website on Injection Drug Use Related Infective Endocarditis.

BACKGROUND: Few patient-facing educational materials and interventions exist for the prevention of injection drug use-related infective endocarditis (IDU-IE). We developed a patient and clinician-informed website for patients about IDU-IE to promote education and prevention strategies. METHODS: This mixed-methods study integrated surveys and semi-structured interviews with patients and clinician to develop a patient website about IDU-IE. Patient participants included hospitalized adults with an opioid use disorder, history of injection drug use, and an injection drug use-related infection. Interprofessional healthcare clinicians including trainees participated. A baseline survey and semi-structured interviews were conducted with patients to understand knowledge of IDU-IE and preferences in educational materials content and format. Interviews were analyzed using rapid qualitative analysis. Results informed development of the patient website. Finally, patients and clinicians provided 2 rounds of survey feedback after reviewing the website, assessing the likelihood of using and recommending it to others, helpfulness of information in the website sections, and content satisfaction. RESULTS: Patient participants (n = 15) reported low baseline understanding of injection practice and risk of IDU-IE. After reviewing the website (n = 17), patients reported they were very likely to recommend the website as a reference for themselves (mean of 4.3; 4 = very likely) and for others (mean = 4.3). They found the following sections, on average, to be very helpful (4 = very helpful): complications from injection drug use (4.4), safer injection practice (4.4), and information about infective endocarditis (4.4). Patients on average were satisfied with the website content overall (4.8). Clinicians (n = 27) reported, on average, being very likely to recommend this website to a patient (4.4) and to use the website to counsel patients (4.1). CONCLUSIONS: A patient and clinician-informed website on IDU-IE is acceptable for patients and clinicians to use as a patient education resource to help prevent IDU-IE-related harms.

Understanding Clinician Knowledge, Attitudes, and Practices Relating to Nonpharmaceutical Fentanyl and Harm Reduction.

BACKGROUND: Nonpharmaceutical fentanyl (NPF) is driving the national epidemic of opioid overdose deaths. Clinicians can play a role in fostering awareness of this growing risk and delivering interventions to reduce mortality. However, there is limited research assessing clinician knowledge, attitudes, and practices relating to NPF and harm reduction strategies. METHODS: A 34-question survey was designed to assess knowledge, attitudes, and practices related to NPF and harm reduction strategies of adult and pediatric hospital-based and emergency clinicians at a single academic medical center. Results were summarized using descriptive statistics. Chi square and Fishers exact tests were used to compare groups. RESULTS: There were 136 survey responses. The majority (88%) of respondents correctly answered a question on NPF potency. Most respondents were aware that NPF exposure was very (84%) or somewhat likely (10%) for someone using illicit opioids and very (44%) or somewhat likely (46%) for nonopioid drugs. Respondents viewed overdose prevention as highly important for patients using illicit opioids (93%) and nonopioid drugs (86%) but few (21%) were very/extremely familiar with overdose prevention strategies and just over half (57%) were comfortable/very comfortable counseling about overdose prevention. There was wide variability in utilization of harm reduction/treatment strategies (7.3% frequently providing fentanyl test kits to 70% frequently prescribing naloxone). Higher levels of comfort and familiarity with overdose prevention were associated with more frequent counseling on harm reduction strategies. Pediatric-only clinicians had less familiarity (5% very/extremely familiar) and comfort (35% comfortable/very comfortable) with overdose prevention, and limited use of harm reduction strategies (0%-31% using each strategy frequently). CONCLUSIONS: While clinicians had knowledge and awareness of NPF and rated overdose prevention as highly important, utilization of harm reduction and treatment strategies was variable. This study highlights opportunities for education and system-based support to improve clinician-driven harm reduction practices for patients at risk of overdose.

Successful administration of extended-release buprenorphine in the emergency department.

INTRODUCTION: The ongoing opioid epidemic in the United States has resulted in a substantial increase in overdose deaths and related morbidity and mortality. Given that emergency departments (ED) frequently serve as the initial point of contact for individuals experiencing opioid overdose or seeking treatment for opioid use disorder (OUD), ED clinicians have a pivotal role to play in providing prompt and effective treatment for OUD. While ED clinicians routinely administer sublingual and other transmucosal formulations of buprenorphine, extended-release buprenorphine (BUP-XR) remains underutilized in the ED. CASE REPORT: We present a case involving the successful administration of BUP-XR in the ED to a patient experiencing spontaneous opioid withdrawal. The patient tolerated test dosing of sublingual buprenorphine (BUP-SL) and subsequently received BUP-XR in the ED. Following this intervention, the patient was referred to the hospital-affiliated substance use disorder outpatient clinic, where he has since demonstrated successful follow-up and retention in treatment. CONCLUSION: Our report adds to the existing limited literature on the administration of BUP-XR in the ED and highlights the need for more comprehensive clinician teaching and guidance, as well as the establishment of in-hospital protocols for BUP-XR. Despite these challenges, our case indicates that initiating BUP-XR could be a viable and effective option for ED patients with OUD.

Risk of acute kidney injury after lower urinary tract reconstruction with early NSAID therapy: A propensity matched retrospective analysis.

INTRODUCTION: The opioid epidemic response led to increased use of postoperative, non-opioid analgesia. Some pediatric urologists do not routinely use non-steroidal anti-inflammatory drugs (NSAIDs) for fear of causing acute kidney injury (AKI). While previous studies have demonstrated the safety and efficacy of NSAIDs in children, safety after lower urinary tract reconstruction has not been well characterized. OBJECTIVE: ptUsing the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI (increase in creatinine ≥0.3 mg/dL or increase in creatinine ≥1.5x baseline or urine output <0.5 mL/kg/hr for 6 h), we hypothesized there would be a difference in the incidence of postoperative AKI between patients who did and did not receive NSAIDs following surgery. STUDY DESIGN: Patients 2-18 years old who underwent lower urinary tract reconstruction (i.e., bladder augmentation and/or creation of a catheterizable channel) from 2009 to 2021 and had documented urine output were retrospectively reviewed. Chronic kidney disease (CKD) stage was calculated from creatinine and cystatin C within 6 months of surgery using the CKiD U25 equations. Patients who received NSAIDs were propensity matched on 11 characteristics with patients undergoing similar surgeries who did not receive NSAIDs. The primary outcome was incidence of AKI within 48 h of surgery. RESULTS: The unmatched cohorts included 243 patients. Propensity matching identified 166 patients in the NSAID arm and 41 in the no NSAID arm. 26 patients with CKD stage 2-3 were included. There was no significant difference in the incidence of postoperative AKI based on any KDIGO criteria (17.1% no NSAID versus 16.3% NSAID, p = 0.87). Median postoperative opioids fell from 0.88 mg/kg in the no NSAID arm to 0.37 mg/kg morphine equivalents in the NSAID arm, although this was not statistically significant. Log-rank testing by Kaplan-Meier analysis demonstrated no difference in time to incidence of low urine output between the groups (p = 0.32). In the whole population not stratified by NSAID use, no differences were seen in AKI between those with and without CKD (16.7% with versus 17.9% without CKD). DISCUSSION: There was no difference in the incidence of postoperative AKI among patients who did and did not receive NSAIDs after lower urinary tract reconstruction, excluding those with advanced CKD. CONCLUSION: These results support that postoperative NSAIDs were an unlikely source of AKI. However, AKI remained a risk following these surgeries, regardless of NSAID use, likely owing to underlying disease, longer operations, and fluid shifts.

Sexually Transmitted Infection (STI) Incidence, STI Screening, and Human Immunodeficiency Virus Preexposure Prophylaxis Uptake in United States Veterans With Opioid Use Disorder in Long Island, New York.

Background: Opioid use disorder (OUD) confers increased risk of contracting bloodborne and sexually transmitted infections (STIs). Limited data exist on infectious disease screening and preexposure prophylaxis (PrEP) usage among United States Veterans (USVs) with OUD, including persons who inject drugs (PWID). This study aimed to evaluate the epidemiology of human immunodeficiency virus (HIV), hepatitis C virus (HCV), bacterial STIs, and PrEP uptake in USVs with OUD, including PWID. Methods: A retrospective chart review of USVs with OUD seeking care at Northport Veterans Affairs Medical Center between 2012 and 2022 was completed. Sociodemographics, HIV, HCV, STI testing rates and diagnosis, and PrEP uptake were compared between USVs, stratified by injection drug use history. Results: We identified 502 USVs with OUD; 43% had a history of injection drug use. Overall, 2.2% of USVs had HIV and 28.7% had HCV. An STI was diagnosed in 10% of USVs, most frequently syphilis (1.8%). PWID were more likely to be tested for HIV (93.5% PWID vs. 73.1% non-PWID; P < .001), HCV (95.8% PWID vs. 80.8% non-PWID; P < .001), and syphilis (80% PWID vs. 69.2% non-PWID; P = .006). Total gonorrhea and chlamydia testing rates were 31.9% and 33.7%, respectively, without difference between the groups. PrEP was prescribed in 1.2% of USVs. Conclusions: In USVs with OUD, gonorrhea and chlamydia screening occurred less frequently than syphilis, HCV, and HIV. PWID were more likely to be screened for HIV, HCV, and syphilis. PrEP uptake was low. Both PWID and non-PWID may benefit from increased STI screening and linkage to PrEP.

A case of opioid-induced rigidity requiring naloxone administration at the time of anesthesia emergence.

BACKGROUND: Opioid-induced rigidity is typically observed during rapid administration of fentanyl. Herein, we present a case in which rigidity occurred after reversal of rocuronium during emergence from anesthesia. CASE PRESENTATION: A 73-year-old man underwent video-assisted partial lung resection. General anesthesia was induced with propofol, remimazolam, remifentanil, and rocuronium. Fentanyl was administered early during anesthesia. The surgery was completed without complications, and sugammadex sodium was administered for rocuronium reversal. The patient became agitated, but spontaneous breathing was maintained; therefore, the intratracheal tube was removed after the administration of flumazenil. The patient developed stiffness in the neck and jaw muscles along with remarkable skeletal muscle contractions. Dramatic improvement was observed immediately after administration of naloxone. CONCLUSIONS: Even as the simulated effect site concentration of fentanyl decreases during anesthesia emergence, opioid-induced rigidity may still occur. Rapid reversal of remimazolam by flumazenil might have contributed to the rigidity in this case.

Prevalence and factors associated with opioid use disorder among adolescents with sickle cell disease in Mulago hospital, Uganda.

BACKGROUND: Opioid use disorder (OUD) among adolescents with sickle cell disease (SCD) patients increases their risk of complications from sickle cell disease, such as infections, stroke, acute chest syndrome, sudden death, and organ failure. This negatively impacts families, communities, the national health system, and the economy. This study aimed to determine the prevalence and factors associated with opioid use disorder among adolescents with SCD at Mulago Hospital Uganda. METHODS: This study was carried out at the Sickle Cell Clinic of Mulago Hospital, the national referral hospital in Uganda. The study participants were adolescents aged 10 to 19 years. Following informed consent/ assent, a sociodemographic questionnaire, the WHO Alcohol, Smoking and Substance Involvement Screening Test - Young (ASSIST-Y), the Beck Depression Inventory-II (BDI II), and Generalized Anxiety Disorder - 7 (GAD-7) questionnaires were used to collect data. Data was entered in EpiInfo and analyzed in STATA 15. RESULTS: The prevalence of opioid use disorder was 5.3%. The significant risk factor was increasing depressive score AOR: 1.11(95% CI: 1.01-1.22, p = 0.035), while living with a family was protective against opioid use disorders AOR: 0.01; (95% CI: 0.0004, 0.27, p = 0.007). CONCLUSION: There was a significant problem of OUD among adolescents with SCD. There is, therefore, needed to integrate screening of OUD and mental illnesses like depression among adolescents with SCD and to emphasize the importance of family support in their care.

Methadone treatment utilization and overdose trends among Medicaid beneficiaries in New Jersey before and during the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic disrupted the traditional mode of methadone maintenance treatment (MMT) delivery through the imposition of lockdowns and social distancing measures. In response, policy makers granted flexibilities to providers delivering MMT to change their practices to maintain patient participation while accommodating the measures imposed to prevent the spread of COVID-19. This study examines the utilization of MMT and overdoses of patients receiving MMT during the COVID-19 pandemic in one mid-Atlantic state. MATERIALS AND METHODS: We analyzed Medicaid claims data for 2018-2020, calculating weekly trends for starts, discontinuations, and medically-treated overdoses for beneficiaries receiving MMT who had been continuously enrolled in Medicaid for the previous 12 months, to account for changes in the composition of the Medicaid population following the COVID-19 public health emergency (PHE). We completed data analyses from January to June 2022. RESULTS: We observed countervailing trends in new starts, which experienced an immediate, non-significant dip of -22.47 per 100,000 Medicaid beneficiaries (95%CI, -50.99 to 6.04) at the outset of the pandemic followed by an increasing upward trend of 1.41 per 100,000 beneficiaries per week (95%CI, 0.37 to 2.46), and in discontinuations, which also experienced an immediate dip of -3.23 per 1000 MMT enrollees (95%CI, -4.49 to -1.97) followed by an increasing upward trend of 0.14 per 1000 MMT enrollees per week (95%CI, 0.09 to 0.19). The net result of these shifts was a stable, slowly increasing rate of MMT treatment of 0.02 % per week before and after the PHE. We also found no statistically significant association of the PHE with medically-treated overdoses among beneficiaries enrolled in MMT (trend change = 0.02 overdoses per 10,000 MMT enrollees, 95%CI, -0.05 to 0.09). CONCLUSIONS: New Jersey achieved overall stability in MMT treatment prevalence following the pandemic's onset, while some changes in treatment dynamics took place. This outcome may reflect that the extensive flexibilities granted to providers of MMT by the state and federal government successfully maintained access to MMT for Medicaid beneficiaries through the pandemic without increasing risk of medically-treated overdose. These findings should inform policy makers developing the post-COVID-19 legal and regulatory landscape.

Opioid prescription following radical orchiectomy associated with new persistent opioid use.

INTRODUCTION: Opioid dependence represents a public health crisis and can be observed after outpatient urologic procedures. The purpose of this study was to evaluate the risk of persistent opioid usage after radical orchiectomy for testicular cancer. MATERIALS AND METHODS: The TriNetX Research network database was queried for men between 15 and 45 years undergoing radical orchiectomy for a diagnosis of testicular cancer. All patients with N+ or M+ disease, prior opioid use, and patients who underwent chemotherapy, radiotherapy, or retroperitoneal lymph node dissection were excluded. Patients were stratified whether they were prescribed opioids or not at time of orchiectomy. The incidence of new, persistent opioid use, defined as a prescription for opioids between 3 and 15 months after orchiectomy, was evaluated. RESULTS: A total of 2,911 men underwent radical orchiectomy for testicular cancer, of which 89.8% were prescribed opioids at time of orchiectomy. After propensity score matching for age, race, and history of psychiatric diagnosis, 592 patients were included (296 received opioids, 296 did not). Overall, 0% of patients who did not receive postoperative opioids developed new persistent opioid use, whereas 10.5% of patients who received postoperative opioids developed new persistent opioid use. Patients prescribed postoperative opioids for orchiectomy had statistically higher risk difference of developing new persistent opioid use (Risk Difference: 10.5%; 95% CI: 7.0-14.0; Z: 5.7; P < 0.01). CONCLUSIONS: Postoperative opioid prescription following radical orchiectomy is significantly associated with developing new persistent opioid use, with 1 in 10 young men who received postoperative opioids obtaining a new prescription for opioids well beyond the postoperative period. Future efforts should emphasize nonopioid pathways for pain control following this generally minor procedure.

Opioid-Induced Constipation and Associated Symptoms After Orthopedic Trauma.

PURPOSE: Opioid-induced constipation is an adverse effect often experienced among patients taking prescription opioid medication. Despite frequent opioid prescribing after orthopedic injury, there is a dearth of research examining opioid-induced constipation presentations in this population. This analysis examines the frequency of opioid-induced constipation manifestations and association with patient-reported outcomes among participants prescribed opioid medication following orthopedic injury. DESIGN: Secondary analysis of 86 clinical trial participants following orthopedic trauma. METHODS: Participants were assessed 2-weeks postoperatively with the following measures: Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference, PROMIS Physical Function, past 24-hour average pain intensity captured on the numeric pain rating scale, and the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire. Linear regressions examined the association between PAC-SYM scores and both pain intensity and PROMIS T-scores while accounting for injury severity and opioid medication dosage. RESULTS: Most participants (69%) reported experiencing opioid-induced constipation symptoms and 7% reported moderate to severe symptoms. Compared to those without symptoms, participants reporting opioid-induced constipation symptoms were found to have a 3-point increase in PROMIS Pain Interference (95% Confidence Interval [CI]: 0.28-5.90; p = .032), a 3-point decline in PROMIS Physical Function (95% CI: -6.57 to -0.02; p = .049), and a 1.7-point increase in average pain scores (95% CI: 0.50-3.01; p = .007) at 2-weeks following surgery. CONCLUSIONS: Opioid-induced constipation symptoms are common after orthopedic trauma and linked to increased pain interference and pain intensity as well as reduced physical function. CLINICAL IMPLICATIONS: Nurse-led assessments of opioid-induced constipation can support the timely delivery of interventions to alleviate symptoms and potentially improve patient-reported outcomes after injury.

Federal opioid agonist therapy policy: interrupted time series analysis of the impact of the methadone exemption removal across eight provinces in Canada.

BACKGROUND: Federal deregulation of opioid agonist therapies are an attractive policy option to improve access to opioid use disorder care and achieve widespread beneficial impacts on growing opioid-related harms. There have been few evaluations of such policy interventions and understanding effects can help policy planning across jurisdictions. METHODS: Using health administrative data from eight of ten Canadian provinces, this study evaluated the impacts of Health Canada's decision in May 2018 to rescind the requirement for Canadian health professionals to obtain an exemption from the Canadian Drugs and Substance Act to prescribe methadone for opioid use disorder. Over the study period of June 2017 to May 2019, we used descriptive statistics to capture overall trends in the number of agonist therapy prescribers across provinces and we used interrupted time series analysis to determine the effect of this decision on the trajectories of the agonist therapy prescribing workforces. RESULTS: There were important baseline differences in the numbers of agonist therapy prescribers. The province with the highest concentration of prescribers had 7.5 more prescribers per 100,000 residents compared to the province with the lowest. All provinces showed encouraging growth in the number of prescribers through the study period, though the fastest growing province grew 4.5 times more than the slowest. Interrupted time series analyses demonstrated a range of effects of the federal policy intervention on the provinces, from clearly positive changes to possibly negative effects. CONCLUSIONS: Federal drug regulation policy change interacted in complex ways with provincial health professional regulation and healthcare delivery, kaleidoscoping the effects of federal policy intervention. For Canada and other health systems such as the US, federal policy must account for significant subnational variation in OUD epidemiology and drug regulation to maximize intended beneficial effects and mitigate the risks of negative effects.

Association of economic and racial segregation with restricted buprenorphine dispensing in U.S. community pharmacies.

Background: Timely and reliable dispensing of buprenorphine is critical to accessing treatment for opioid use disorder (OUD). Racial and ethnic inequities in OUD treatment access are well described, but it remains unclear if inequities persist at the point of dispensing. Methods: We analyzed data from a U.S. telephone audit that measured restricted buprenorphine dispensing in community pharmacies, defined as inability to fill a buprenorphine prescription requested by a "secret shopper." Using the Index of Concentration at the Extremes (ICE), we constructed county-level measures of racial, ethnic, economic, and racialized economic (joint racial and economic segregation) segregation. Logistic regression models evaluated the association of ICE measures and restricted buprenorphine dispensing, adjusting for county type (urban vs. rural) and pharmacy type (chain vs. independent). Results: Among 858 pharmacies surveyed in 473 counties, pharmacies in the most ethnically segregated and economically deprived counties had 2.66 times the odds (95 % CI: 1.41, 5.17) of restricting buprenorphine dispensing, compared to pharmacies in the most privileged counties after adjustment. Pharmacies in counties with high racialized economic segregation (quintile 2 and 3) also had higher odds of restricting buprenorphine dispensing (aOR 3.09 [95 % CI 1.7, 5.59]; aOR 2.11 [95 % CI 1.17, 3.98]). Similar associations were observed for economic segregation (aOR: 2.18 [95 % CI: 1.21, 3.99]), but not ethnic (0.59 [0.34, 1.05]) or racial (0.61 [0.35, 1.07]) segregation alone. Conclusions: Restricted buprenorphine dispensing was most pronounced in socially and economically disadvantaged communities, potentially exacerbating gaps in OUD treatment access. Policy interventions should target both prescribing and dispensing capacity to advance pharmacoequity.

Neurocognitive performance of patients undergoing intravenous versus oral opioid agonist treatment: a prospective multicenter study on three-month treatment effects.

Introduction: The first-line treatment for opioid dependence is opioid agonist treatment (OAT) with oral opioids. However, in some cases, treatment with intravenous diacetylmorphine (IV-DAM) is indicated. Research on neurocognitive impairments and treatment effects of OAT - particularly with IV-DAM - on neurocognitive functioning, is scarce. The current study is the first to investigate the neurocognitive performance of individuals on OAT with IV-DAM. Using a prospective study design with two timepoints of measurement, the first aim was to assess the nature and extent of neurocognitive functioning in individuals with opioid dependence by comparing participants' neurocognitive performance with normative data of the general population on admission to treatment (baseline) and after an initial three-month period of OAT (study end). The second aim was to examine whether and to what extent neurocognitive performance would improve after three months on OAT. The third aim was to investigate whether, and if so, to what extent the treatment method (IV-DAM vs. oral opioids) would lead to higher neurocognitive improvements at study end. Methods: Forty-seven opioid-dependent individuals (baseline; 33 individuals at study end) participated in this study (mean age: 34.3 years; 27.7% female). Participants underwent neuropsychological testing with a battery of 12 tests covering different neurocognitive domains, including attention, memory, and executive functions. Results: Compared to normative data, opioid-dependent individuals showed impairments in almost every test both at baseline and at study end. At baseline, neurocognitive performance did not differ between individuals receiving IV-DAM or oral opioids for OAT. Compared to baseline, the neurocognitive performance did neither improve nor deteriorate after three months of treatment with neither IV-DAM nor oral opioids. However, a trend towards improvement was found for the memory domain. Discussion: Given that neurocognitive impairments should be considered in treatment planning and therapeutic interventions. Since a reduced cognitive performance may affect both the treatment outcome and the therapeutic relationship unfavorably, specific neurocognitive training at the beginning of treatment should be considered.

Sustained fentanyl exposure inhibits neuronal activity in dissociated striatal neuronal-glial co-cultures through actions independent of opioid receptors.

Besides having high potency and efficacy at the µ- (MOR) and other opioid receptor types, fentanyl has some affinity for some adrenergic receptor types, which may underlie its unique pathophysiological differences from typical opioids. To better understand the unique actions of fentanyl, we assessed the extent to which fentanyl alters striatal medium spiny neuronal (MSNs) activity via opioid or α1 adrenoceptors in dopamine type 1 or type 2 receptor- (D1 or D2) -expressing MSNs. In neuronal and mixed-glial co-cultures from the striatum, acute fentanyl (100 nM) exposure decreased the frequency of spontaneous action potentials. Overnight exposure of co-cultures to 100 nM fentanyl severely reduced the proportion of MSNs with spontaneous action potentials, which was unaffected by co-exposure to the opioid receptor antagonist naloxone (10 µM), but fully negated by co-administering the pan-α1 adrenoceptor inverse agonist prazosin (100 nM) and partially reversed by the selective α1A/C adrenoceptor antagonist RS 100329 (300 nM). Acute fentanyl (100 nM) exposure modestly reduced the frequency of action potentials and caused firing rate adaptations in D2, but not D1, MSNs. Prolonged (2-5 h) fentanyl (100 nM) application dramatically attenuated firing rates in both D1 and D2 MSNs. To identify possible cellular sites of α1 adrenoceptor action, α1 adrenoceptors were localized in subpopulations of striatal astroglia and neurons by immunocytochemistry, and Adra1a mRNA by in situ hybridization in astrocytes. Thus, sustained fentanyl exposure can inhibit striatal MSN activity via a non-opioid receptor-dependent pathway, that may be modulated via complex actions in α1 adrenoceptor-expressing striatal neurons and/or glia.

Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid-Free Analgesics.

The opioid crisis has highlighted the urgent need to develop non-opioid alternatives for managing pain, with an effective, safe, and non-addictive pharmacotherapeutic profile. Using an extensive structure-activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid-independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile12 residue of NT(7-12) was substituted by cyclopentylalanine, Pro7 and Pro10 were replaced by allyl-glycine followed by side-chain to side-chain cyclization is the most selective analog targeting NTS2 identified to date (Ki 2.9 nM), showing 30,000-fold selectivity over NTS1. Of particular importance, this macrocyclic analog is also able to potentiate the analgesic effects of morphine in a dose- and time-dependent manner. Exerting complementary analgesic actions via distinct mechanisms of nociceptive transmission, NTS2-selective macrocycles can therefore be exploited as opioid-free analgesics or as opioid-sparing therapeutics, offering superior pain relief with reduced adverse effects to pain patients.