Evaluation of respondent-driven sampling in seven studies of people who use drugs from rural populations: findings from the Rural Opioid Initiative.

BACKGROUND: Accurate prevalence estimates of drug use and its harms are important to characterize burden and develop interventions to reduce negative health outcomes and disparities. Lack of a sampling frame for marginalized/stigmatized populations, including persons who use drugs (PWUD) in rural settings, makes this challenging. Respondent-driven sampling (RDS) is frequently used to recruit PWUD. However, the validity of RDS-generated population-level prevalence estimates relies on assumptions that should be evaluated. METHODS: RDS was used to recruit PWUD across seven Rural Opioid Initiative studies between 2018-2020. To evaluate RDS assumptions, we computed recruitment homophily and design effects, generated convergence and bottleneck plots, and tested for recruitment and degree differences. We compared sample proportions with three RDS-adjusted estimators (two variations of RDS-I and RDS-II) for five variables of interest (past 30-day use of heroin, fentanyl, and methamphetamine; past 6-month homelessness; and being positive for hepatitis C virus (HCV) antibody) using linear regression with robust confidence intervals. We compared regression estimates for the associations between HCV positive antibody status and (a) heroin use, (b) fentanyl use, and (c) age using RDS-1 and RDS-II probability weights and no weights using logistic and modified Poisson regression and random-effects meta-analyses. RESULTS: Among 2,842 PWUD, median age was 34 years and 43% were female. Most participants (54%) reported opioids as their drug of choice, however regional differences were present (e.g., methamphetamine range: 4-52%). Many recruitment chains were not long enough to achieve sample equilibrium. Recruitment homophily was present for some variables. Differences with respect to recruitment and degree varied across studies. Prevalence estimates varied only slightly with different RDS weighting approaches, most confidence intervals overlapped. Variations in measures of association varied little based on weighting approach. CONCLUSIONS: RDS was a useful recruitment tool for PWUD in rural settings. However, several violations of key RDS assumptions were observed which slightly impacts estimation of proportion although not associations.

Buprenorphine misinformation and willingness to treat patients with opioid use disorder among primary care-aligned health care professionals.

BACKGROUND: Buprenorphine is a highly effective medication for opioid use disorder that is underused by health care professionals (HCPs). Medications for opioid use disorder (MOUD) misinformation may be an important barrier to buprenorphine access, but most implementation strategies have aimed to reduce negative attitudes towards patients with opioid use disorder (OUD) rather than misinformation specific to buprenorphine use. In this study, we assessed the degree to which HCPs endorsed misinformation related to buprenorphine, and whether this is associated with willingness to provide care to patients with OUD. METHODS: In September-December of 2022, we surveyed HCPs practicing in Ohio (n = 409). Our primary outcomes included a previously validated 5-item measure of HCP willingness to treat patients with OUD, and three other measures of willingness. Our key independent variable was a study-developed 5-item measure of endorsement of misinformation related to buprenorphine, which assessed beliefs in buprenorphine's efficacy in managing withdrawal symptoms and reducing overdose deaths as well as beliefs about the role of buprenorphine in achieving remission. We computed descriptive and bivariable statistics and fit regression models predicting each outcome of interest. RESULTS: On average, HCPs scored 2.34 out of 5.00 (SD = 0.80) on the composite measure of buprenorphine misinformation. 48.41% of participants endorsed at least one piece of misinformation. The most endorsed items were that buprenorphine is ineffective at reducing overdose deaths (M = 2.75, SD =0 .98), and that its use substitutes one drug for another (M = 2.41, SD = 1.25). HCP endorsement of buprenorphine misinformation significantly and negatively predicted willingness to work with patients with OUD (b = - 0.34; 95% CI - 0.46, - 0.21); intentions to increase time spent with this patient population (b = - 0.36; 95% CI - 5.86, - 1.28); receipt of an X-waiver (OR = 0.54, 95% CI 0.38, 0.77); and intention to get an X-waiver (OR: 0.56; 95% CI: 0.33-0.94). CONCLUSIONS: Misinformation is common among HCPs and associated with lower willingness to treat patients with OUD. Implementation strategies to increase MOUD use among HCPs should specifically counter misinformation related to buprenorphine. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT05505227. Registered 17 August 2022, https://clinicaltrials.gov/ct2/show/NCT05505227.

Differences in buprenorphine prescribing readiness among primary care professionals with and without X-waiver training in the US.

BACKGROUND: Medications for opioid use disorder (OUD) are effective at preventing overdose and infectious disease but are vastly under-prescribed in the US. For decades, prescribers faced additional training and regulation to prescribe buprenorphine which stigmatized the medication and lessened support for a harm reduction approach to treating opioid use disorder. The Drug Enforcement Administration removed the X-waiver requirement for prescribing buprenorphine in late 2022, which removed stigma and lessened important barriers to prescribing but also left training at the discretion of individual organizations. Our study aimed to assess differences in knowledge, confidence, and stigma regarding buprenorphine between those who went through the X-waiver training and those who did not, among practicing primary care providers (PCPs). METHODS: We assessed buprenorphine prescribing readiness among primary care aligned outpatient providers in Ohio, USA. Using survey data, we conducted bivariate and regression analyses predicting primary prescribing outcomes. Primary outcomes measured knowledge of and confidence in buprenorphine, as well as perceived adequacy of one's training. Secondary outcomes were attitudes toward patients with OUD, including bias toward OUD patients, stress when working with them, and empathy toward them. Participants (n = 403) included physicians, nurse practitioners, and physician assistants practicing in primary care aligned disciplines. RESULTS: Survey data showed that PCPs who received X-waiver training were more likely to understand and have confidence in the mechanism of buprenorphine, and consider their training on treating OUD to be adequate. PCPs with an X-waiver showed more empathy, less negative bias, and experienced less stress when working with patients with OUD. CONCLUSION: Removing restrictive policies for prescribing buprenorphine is an important step to expanding access and reducing the stigma associated with opioid use disorder treatment. Yet, our findings suggest that the training received alongside regulation may be important for improving prescribing confidence and reducing stigma. Strategies to increase buprenorphine prescribing are unlikely to be effective without also expanding access to prescribing support for primary care providers across the career course.

A Descriptive Study on Opioid Misuse Prevalence and Office-Based Buprenorphine Access in Ohio Prior to the Removal of the Drug Addiction Treatment Act of 2000 Waiver.

Background Medications for the treatment of opioid use disorder (MOUD) are effective evidence-based strategies to reduce opioid overdose deaths. Strategies to optimize MOUD availability and uptake are needed. Objective We aim to describe the spatial relationship between the estimated prevalence of opioid misuse and office-based buprenorphine access in the state of Ohio prior to the removal of the Drug Addiction Treatment Act of 2000 (DATA 2000) waiver requirement. Methods We conducted a descriptive ecological study of county-level (N=88) opioid misuse prevalence and office-based buprenorphine prescribing access in Ohio in 2018. Counties were categorized into urban (with and without a major metropolitan area) and rural. The county-level prevalence estimates of opioid misuse per 100,000 were derived from integrated abundance modeling. Utilizing data from the Ohio Department of Mental Health and Addiction Services, as well as the state's Physician Drug Monitoring Program (PDMP), buprenorphine access per 100,000 was estimated by the number of patients in each county that could be served by office-based buprenorphine (prescribing capacity) and the number of patients served by office-based buprenorphine (prescribing frequency) for opioid use disorder. The ratios of opioid misuse prevalence to both prescribing capacity and frequency were calculated by county and mapped. Results Less than half of the 1,828 waivered providers in the state of Ohio in 2018 were prescribing buprenorphine, and 25% of counties had no buprenorphine access. The median estimated opioid misuse prevalence and buprenorphine prescribing capacity per 100,000 were highest in urban counties, particularly those with a major metropolitan area. Although the median estimated opioid misuse prevalence was lower in rural counties, all counties in the highest quartile of estimated misuse prevalence were rural. In addition, the median buprenorphine prescribing frequency was highest in rural counties. While the ratio of opioid misuse prevalence to buprenorphine prescribing capacity was lowest in urban counties, the ratio of opioid misuse prevalence to buprenorphine prescribing frequency was lowest in rural counties. Opioid misuse prevalence and buprenorphine prescribing frequency demonstrated similar spatial patterns, with highest levels in the southern and eastern portions of the state, while office-based buprenorphine prescribing capacity did not. Conclusion Urban counties had higher buprenorphine capacity relative to their burden of opioid misuse; however, access was limited by buprenorphine prescribing frequency. In contrast, in rural counties, a minimal gap was evident between prescribing capacity and frequency, suggesting that buprenorphine prescribing capacity was the major factor limiting access. While the recent deregulation of buprenorphine prescribing should help improve buprenorphine access, future research should investigate whether deregulation similarly impacts buprenorphine prescribing capacity and buprenorphine prescribing frequency.

Positive contact and empathy as predictors of primary care providers' willingness to prescribe medications for opioid use disorder.

Introduction: Patients with opioid use disorder (OUD) have a heightened need for quality health care, including access to evidence-based medications to reduce cravings and prevent overdose. However, primary care providers (PCPs) are reluctant to work with patients with OUD and implement medication prescribing into primary care practice. Previous studies have sought to identify potential ways to overcome these barriers, but often utilize interventions that facilitate both positive contact with as well as empathy for patients with OUD. In this study, we jointly assess positive contact and empathy to determine their unique impact on treatment attitudes and behaviors among PCPs, after controlling for other known predictors. Methods: We surveyed 409 PCPs currently practicing in Ohio in 2022. Our primary dependent variables were willingness to work with patients with OUD, receipt of an X-waiver to prescribe buprenorphine, and interest in receiving an X-waiver. Our primary independent variables were positive contact and empathy toward patients with OUD. We computed bivariate correlations and multivariable linear regression (for continuous dependent variables) and logistic regression (for binary dependent variables) to understand the relationship between positive contact, empathy, and our outcome variables while accounting for other known predictors and relevant participant demographics. Results: Positive contact was positively correlated with willingness to work with patients with OUD, receipt of the X-waiver, an interest in receiving the X-waiver, more frequent checking with patients about the need for naloxone, and higher odds of naloxone prescribing. These relationships held after accounting for PCP demographics, explicit bias toward patients with OUD, and overall levels of contact with patients with OUD. Empathy, conversely, was not a significant predictor of any treatment outcomes in the fully adjusted models. Conclusion: Interventions and medical education programs aimed at improving treatment outcomes for patients with OUD should facilitate positive contact between PCPs and patients with OUD.

The Relationship Between Hepatitis C Virus Rates and Office-Based Buprenorphine Access in Ohio.

BACKGROUND: The United States is experiencing an epidemic of hepatitis C virus (HCV) infections due to injection drug use, primarily of opioids and predominantly in rural areas. Buprenorphine, a medication for opioid use disorder, may indirectly prevent HCV transmission. We assessed the relationship of HCV rates and office-based buprenorphine prescribing in Ohio. METHODS: We conducted an ecological study of the county-level (n = 88) relationship between HCV case rates and office-based buprenorphine prescribing in Ohio. We fit adjusted negative binomial models between the county-level acute and total HCV incidence rates during 2013-2017 and 1) the number of patients in each county that could be served by office-based buprenorphine (prescribing capacity) and 2) the number served by office-based buprenorphine (prescribing frequency) from January-March, 2018. RESULTS: For each 10% increase in acute HCV rate, office-based buprenorphine prescribing capacity differed by 1% (95% CI: -1%, 3%). For each 10% increase in total HCV rate, office-based buprenorphine prescribing capacity was 12% (95% CI: 7%, 17%) higher. For each 10% increase in acute HCV rate, office-based buprenorphine prescribing frequency was 1% (95% CI: -1%, 3%) higher. For each 10% increase in total HCV rate, office-based buprenorphine prescribing frequency was 14% (95% CI: 7%, 20%) higher. CONCLUSIONS: Rural counties in Ohio have less office-based buprenorphine and higher acute HCV rates versus urban counties, but a similar relationship between office-based buprenorphine prescribing and HCV case rates. To adequately prevent and control HCV rates, certain rural counties may need more office-based buprenorphine prescribing in areas with high HCV case rates.

Physician blame and vulnerability: novel predictors of physician willingness to work with patients who misuse opioids.

BACKGROUND: Successfully combating the opioid crisis requires patients who misuse opioids to have access to affirming and effective health care. However, there is a shortage of physicians who are willing to work with these patients. We investigated novel predictors of what might be contributing to physicians' unwillingness to engage with this patient population to better identify and direct interventions to improve physician attitudes. METHODS: 333 physicians who were board certified in the state of Ohio completed a survey about their willingness to work with patients who misuse opioids. The hypothesized relationships between the proposed predictors and willingness to work with this patient population were tested using multivariate regression, supplemented with qualitative analysis of open-text responses to questions about the causes of addiction. RESULTS: Perceptions of personal invulnerability to opioid misuse and addiction, opioid misuse and addiction controllability, and health care provider blame for the opioid crisis were negatively associated with physician willingness to work with patients who misuse opioids after controlling for known predictors of physician bias toward patients with substance use disorders. Physicians working in family and internal medicine, addiction medicine, and emergency medicine were also more willing to work with this patient population. CONCLUSIONS: Distancing oneself and health care professionals from opioid misuse and placing blame on those who misuse are negatively associated with treatment willingness. Interventions to improve physician willingness to work with patients who misuse opioids can target these beliefs as a way to improve physician attitudes and provide patients with needed health care resources.

"Now We Are Seeing the Tides Wash In": Trauma and the Opioid Epidemic in Rural Appalachian Ohio.

Background: Ohio's opioid epidemic continues to progress, severely affecting its rural Appalachian counties-areas marked by high mortality rates, widespread economic challenges, and a history of extreme opioid overprescribing. Substance use may be particularly prevalent in the region due to interactions between community and interpersonal trauma. Purpose/Objectives: We conducted qualitative interviews to explore the local context of the epidemic and the contributing role of trauma. Methods: Two interviewers conducted in-depth interviews (n = 34) with stakeholders in three rural Appalachian counties, including healthcare and substance use treatment professionals, law enforcement officials, and judicial officials. Semi-structured interview guides focused on the social, economic, and historical context of the opioid epidemic, perceived causes and effects of the epidemic, and ideas for addressing the challenge. Results: Stakeholders revealed three pervasive forms of trauma related to the epidemic in their communities: environmental/community trauma (including economic and historical distress), physical/sexual trauma, and emotional trauma. Traumas interact with one another and with substance use in a self-perpetuating cycle. Although stakeholders in all groups discussed trauma from all three categories, their interpretation and proposed solutions differed, leading to a fragmented epidemic response. Participants also discussed the potential of finding hope and community through efforts to address trauma and substance use. Conclusions: Findings lend support to the cyclical relationship between trauma and substance use, as well as the importance of environmental and community trauma as drivers of the opioid epidemic. Community-level and trauma-informed interventions are needed to increase stakeholder consensus around treatment and prevention strategies, as well as to strengthen community organization networks and support community resilience. Supplemental data for this article is available online at https://doi.org/10.1080/10826084.2021.1887248.

"I Was Raised in Addiction": Constructions of the Self and the Other in Discourses of Addiction and Recovery.

The aim of this article is to address how conceptualizations of addiction shape the lived experiences of people who use drugs (PWUDs) during the current opioid epidemic. Using a discourse analytic approach, we examine interview transcripts from 27 PWUDs in rural Appalachian Ohio. We investigate the ways in which participants talk about their substance use, what these linguistic choices reveal about their conceptions of self and other PWUDs, and how participants' discursive caches might be constrained by or defined within broader social discourses. We highlight three subject positions enacted by participants during the interviews: addict as victim of circumstance, addict as good Samaritan, and addict as motivated for change. We argue participants leverage these positions to contrast themselves with a reified addict-other whose identity carries socially ascribed characteristics of being blameworthy, immoral, callous, and complicit. We implicate these processes in the perpetuation of intragroup stigma and discuss implications for intervention.

Access to single-visit IUD insertion at obstetrician-gynecology practices in Ohio: An audit study.

OBJECTIVE: Single-visit intrauterine device (IUD) insertion protocols are recommended. We assessed the availability of single-visit IUD insertions, and whether access to these services varies by age, race or parity. STUDY DESIGN: Using audit study methodology, we called a random sample of 396 obstetrician-gynecology practices in Ohio while posing as a potential client seeking an IUD insertion appointment. Callers used eight standardized scripts and noted justifications for protocols offered by clinic staff. Practices were randomized to follow a balanced 3×2 factorial design, whereby practices were assigned to one of two conditions: (1) age (18 vs. 30 years of age); (2) race (white vs. black); and (3) parity. Multivariable logistic regression was used to control for clinics rural vs. urban location while considering the effects of these variables on service provision. RESULTS: Almost all (95%) of the practices called offered IUD placement, of which 92% required multiple appointments for IUD insertion. Although access to single-visit IUD services did not vary by age or race, we found that parity was associated with clinics' willingness to schedule a single-visit insertion visit (OR = 3.84, 95% CI = 1.23, 12.04). The most frequent justification provided by clinic staff for their multiple-appointment protocol was the need to verify insurance coverage or order the device directly through the patient's insurance company. CONCLUSION: Ohio patients seeking IUD placement must typically make more than one clinic visit. IMPLICATIONS: Efforts are needed to reassure Ohio clinics that IUDs are routinely covered by insurers and to increase access to same-day IUD placement for women in Ohio, as the requirement to attend multiple clinics appointments to obtain a desired contraceptive may pose an insurmountable barrier to care for those with the fewest resources.

"You are not clean until you're not on anything": Perceptions of medication-assisted treatment in rural Appalachia.

BACKGROUND: Medication-assisted treatment (MAT) is an evidence-based strategy to treat opioid use disorder (OUD). However, MAT-related stigma reduces MAT uptake, which is particularly low in rural areas. To date, perceptions and attitudes towards MAT in rural settings have not been described. OBJECTIVE: This qualitative study aims to characterize perceptions and attitudes towards MAT and the environmental factors contributing to these views in Appalachian Ohio. METHODS: From February to July 2018, semi-structured interviews were conducted with 34 stakeholders (12 healthcare professionals, 12 substance use treatment providers, 7 law enforcement agents and judicial officials, and 3 members of relevant organizations) in three rural counties in Appalachian Ohio. Interviews were transcribed, coded, and analyzed to characterize the risk environment and participants' perceptions and attitudes towards MAT. RESULTS: Participants expressed or described pervasive MAT-related stigma in the region. Participants consistently described three elements of the environment affecting stigma: (1) a "conservative" culture in which abstinence is necessary to be in recovery successfully, (2) fear of medication diversion and abuse, and (3) drug court policies that keep MAT out of the criminal justice system. CONCLUSION: MAT-related stigma will need to be addressed to tackle the opioid epidemic through evidence-based treatment effectively.

Social determinants of health priorities of state Medicaid programs.

BACKGROUND: Growing understanding of the influence of social determinants of health (SDH) on healthcare costs and outcomes for low income populations is leading State Medicaid agencies to consider incorporating SDH into their program design. This paper explores states' current approaches to SDH. METHODS: A mixed-methods approach combined a web-based survey sent through the Medicaid Medical Director Network (MMDN) listserv and semi-structured interviews conducted at the MMDN Annual Meeting in November 2017. RESULTS: Seventeen MMDs responded to the survey and 14 participated in an interview. More than half reported current collection of SDH data and all had intentions for future collection. Most commonly reported SDH screening topics were housing instability and food insecurity. In-depth interviews underscored barriers to optimal SDH approaches. CONCLUSION: These results demonstrate that Medicaid leaders recognize the importance of SDH in improving health, health equity, and healthcare costs for the Medicaid population but challenges for sustainable implementation remain.

Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature.

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42⋅guanosine triphosphate and SNX9 activate N-WASP-WIP- and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P2, and PI(3)P signals are needed for SNX9 assembly via its PX-BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease-associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3)P production, suggesting PI(3)P kinase inhibitors as a therapeutic strategy in Lowe syndrome.

Affordable orphan drugs: a role for not-for-profit organizations.

AIMS: The success of the Regulation on Orphan Medicinal Products in the European Union is evidenced by the 127 orphan drugs that have had market authorization since 2000. However, the incentives aimed at stimulating research and development have had the unintended consequence of increasing drug cost, resulting in many orphan drugs not being cost-effective. Orphan drugs command an increasing share of the pharmaceutical market and account for a disproportionate amount of healthcare expenditure. Orphan drug ownership by socially motivated, not-for-profit organizations may facilitate access to more affordable orphan drugs, for the benefit of patients and healthcare systems alike. This study aims to describe opportunities for such organizations to become orphan drug Market Authorization Holders. METHODS: We reviewed data on the ownership of EMA designated and approved orphan drugs, identified funding opportunities and business models for not-for-profit organizations, and summarised relevant legal and policy documents concerning intellectual property rights and drug regulation. RESULTS: Using repurposed drugs as a paradigm, this narrative review navigates the regulatory hurdles, describes the legal context and identifies funding opportunities, in a bid to facilitate and encourage not-for-profit organizations to lead on the development of affordable orphan drugs. CONCLUSIONS: Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs.

Eradicating acute myeloid leukemia in a Mll(PTD/wt):Flt3(ITD/wt) murine model: a path to novel therapeutic approaches for human disease.

The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.