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Adrianne Kehne,1,2 Steven J Bernstein,1– 3 Jennifer Thomas,1 Mark C Bicket,3,4,* Amy SB Bohnert,2– 4,* Erin Fanning Madden,5,* Victoria D Powell,6,7,* Pooja Lagisetty1– 3 1Division of General Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; 2Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA; 3Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA; 4Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA; 5Department of Family Medicine and Public Health Sciences, Wayne State University School of Medicine, Detroit, MI, USA; 6Palliative Care Program, Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; 7Geriatrics Research, Education, and Clinical Center, LTC Charles S. Kettles VA Medical Center, Ann Arbor, MI, USA*These authors contributed equally to this workCorrespondence: Adrianne Kehne, Division of General Internal Medicine, University of Michigan, 2800 Plymouth Road, Building 16, Floor 4, Ann Arbor, MI, 48109, USA, Tel +1 301 503 3936, Email adkehne@med.umich.eduPurpose: About 5– 8 million US patients take long-term opioid therapy for chronic pain. In the context of policies and guidelines instituted to reduce inappropriate opioid prescribing, abrupt discontinuations in opioid prescriptions have increased and many primary care clinics will not prescribe opioids for new patients, reducing access to care. This may result in uncontrolled pain and other negative outcomes, such as transition to illicit opioids. The objective of this study was to generate policy, intervention, and research recommendations to improve access to care for these patients.Participants and Methods: We conducted a RAND/UCLA Modified Delphi, consisting of workshops, background videos and reading materials, and moderated web-based panel discussions held September 2020–January 2021. The panel consisted of 24 individuals from across Michigan, identified via expert nomination and snowball recruitment, including clinical providers, health science researchers, state-level policymakers and regulators, care coordination experts, patient advocates, payor representatives, and community and public health experts. The panel proposed intervention, policy, and research recommendations, scored the feasibility, impact, and importance of each on a 9-point scale, and ranked all recommendations by implementation priority.Results: The panel produced 11 final recommendations across three themes: reimbursement reform, provider education, and reducing racial inequities in care. The 3 reimbursement-focused recommendations were highest ranked (theme average = 4.2/11), including the two top-ranked recommendations: increasing reimbursement for time needed to treat complex chronic pain (ranked #1/11) and bundling payment for multimodal pain care (#2/11). Four provider education recommendations ranked slightly lower (theme average = 6.2/11) and included clarifying the spectrum of opioid dependence and training providers on multimodal treatments. Four recommendations addressed racial inequities (theme average = 7.2/11), such as standardizing pain management protocols to reduce treatment disparities.Conclusion: Panelists indicated reimbursement should incentivize traditionally lower-paying evidence-based pain care, but multiple strategies may be needed to meaningfully expand access.Keywords: long-term opioid therapy, pain care access, reimbursement models, expert panel

Objective: This study evaluated the prevalence and incidence of opioid use disorder (OUD), rates of opioid overdose (OD), and rates of non-fatal (NF) OD in American Indian/Alaskan Native (AI/AN) populations., Methods: We used de-identified patient data from Oracle Cerner Real-World Data™. Rates were estimated over time, and stratified by sex, age, marital status, insurance, and region. Mann-Kendall trend tests and Theil-Sen slopes assessed changes over time for each group while autoregressive modeling assessed differences between groups., Results: The study identified trends in OUD and OD among 700,225 AI/AN patients aged 12 and above. Between 2012 and 2022, there was a significant upward trend in both OUD and OD rates (p < 0.05) , with OUD diagnosed in 1.75% and OD in 0.38% of the population. The Western region of the US exhibited the highest rates of OUD and OD. The 35-49 age group showed the highest rates of OUD, while the 12-34 age group had the highest rates of OD. Marital status analysis revealed higher rates of OUD and OD among separated, widowed, or single patients. Additionally, individuals with Medicare or Medicaid insurance demonstrated the highest rates of OUD and OD., Conclusion: Results show that rates of OUD, OD, and NF OD continue to rise among AI/AN individuals, with some regional and demographic variation. Our study provides foundational estimates of key AI/AN populations bearing greater burdens of opioid-related morbidity that federal, state, and tribal organizations can use to direct and develop targeted resources that can improve the health and well-being of AI/AN communities., (© 2024. W. Montague Cobb-NMA Health Institute.)

Background: Suicide is a major driver of mortality among college students and is the leading cause of death among American Indian, Alaska Native, and Native Hawaiian (AI/AN/NH) young adults., Methods: Data on suicidal ideation, suicide attempt, and self-injury among AI/AN/NH college students ( n  = 8103) were analyzed via multivariable logistic regressions employing the American College Health Association National College Health Assessment survey from 2015 to 2019. Adjusted odds ratios (aORs) were used to assess how opioid misuse may act as a risk or protective factor for suicidality and self-injury., Results: Between 2015 and 2019, suicidal ideation was the most prevalent dimension of suicidality affecting AI/AN/NH college students (ranges from 12.69% to 18.35%), followed by self-injury (7.83%-11.41%) and suicide attempt (2.40%-4.10%). AI/AN/NH college students who reported opioid misuse were significantly more likely to experience suicidal ideation (aOR: 1.417; 95% confidence interval [CI]: 1.154-1.740) and self-injury (aOR: 1.684; 95% CI: 1.341-2.116) than those who did not engage in such behavior., Conclusions: We identified opioid misuse as a potential risk factor for suicidal ideation and intentional self-injury among populations of AI/AN/NH college students. Programs seeking to reduce suicide prevalence among Indigenous college students may benefit from the inclusion of evidence-based interventions that prevent and treat issues related to opioid use., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Background: Stigma enacted in primary care settings remains a barrier to care for people who use drugs (PWUD). Little is known about the acceptability of potential stigma interventions to target structural drivers of stigma affecting the organizational- or provider-level., Methods: In-depth interview data were collected from 21 individuals working in Michigan primary care facilities. Participants included clinical (e.g., physicians, nurses) and non-clinical (e.g., administrators, receptionists) staff. Interviews explored perceptions of stigma toward PWUD and the acceptability of interventions to mitigate such stigma. Thematic analysis was used to identify stigma themes., Results: Participants largely reported substance-use stigma as a matter of individual attitudes or knowledge limitations and described such stigma as rarely occurring during interpersonal interactions. Participants were still acutely aware of upstream societal and organizational factors creating structural barriers to care and/or worsening outcomes among PWUD, but seldom labeled these as stigma. Some provider and structural stigma reduction interventions were enthusiastically supported because they address participant ideas of substance-use stigma drivers (e.g., lack of knowledge) or provide resources that could improve care quality or provide resources for PWUD. Conversely, participants opposed some potential stigma interventions, e.g., less-frequent urine drug testing and increasing clinical visit time, deemed infeasible because of outside forces like insurers or regulators., Conclusions: Although most participants conceptualized substance-use stigma as an individual or interpersonal process best addressed with training, their awareness of social determinants of health seemed to fuel an openness to some structural interventions to reduce organizational and provider stigma toward PWUD in primary care settings., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s).)

We bring together insights from the sociology of diagnosis and the sociology of ignorance to examine the early diagnostic unfolding of 'Long COVID' (LC). Originally described by patient activists, researchers set out to ponder its unwieldy clinical boundaries. Using a scoping review method in tandem with qualitative content analytic techniques, we analyse medicine's initial struggles to construct a LC diagnosis. Paying attention to the dynamics of ignorance, we highlight three consequential conceptual manoeuvres in the early classifications of LC: causal agnosticism concerning the relationship between COVID-19 and LC, evasion of lumping LC with similar conditions; and the predictable splitting off of medically explainable cases from the LC designation. These manoeuvres are not maleficent, inept or unreasonable. They are practical but impactful responses to the classificatory dilemmas present in the construction of diagnoses amidst ignorance. Although there are unique aspects to LC, we suggest that its early fate is nevertheless emblematic of medicine's diagnostic standardisation processes more generally. To varying degrees, diagnoses are ignorance management strategies; they create a pathway through the uncertainty at the core of disease realities. However, while diagnoses circumscribe some types of ignorance, they produce others through the creation of blind spots and paths not taken., (© 2022 Foundation for the Sociology of Health & Illness.)

Objectives: Stigma and lack of knowledge are barriers to clinicians when caring for individuals with opioid use disorder (OUD). In 2018, only about 15 out of 180 American medical schools had comprehensive addiction programs. The AAMC reports that institutions are increasingly incorporating competencies to address the OUD and opioid epidemic. There have been few evaluated curriculums focused on reducing stigmatizing attitudes. This study evaluated whether a 4-hour case-based curriculum focused on improving stigmatizing attitudes toward patients with OUD could reduce medical student perceptions around viewing addiction as a punitive condition and other substitution-based misconceptions around opioid agonist-based medication., Methods: Medical students completed a 4-hour curricular workshop which included learning objectives focusing on barriers to healthcare/stigmatizing attitudes, effective behavioral therapy options, and appropriate use of opioid medications. We measured changes in knowledge and attitudes using validated scales on stigma. Non-parametric repeated measure tests determined statistically significant differences between pre and post assessments between OUD related perceptions and a control condition (diabetes)., Results: Of 135 eligible participants, 99 (76%) students completed both pre- and post-surveys. Mean scores across knowledge questions improved (60%-81%, P  < .001) and stigmatizing attitudes regarding perceived violence of people with OUD decreased (2.04-1.82, P  = .016). There was significant improvement in mean scores for OUD-related opinions including desire to work with and effectively treat patients with OUD (3.58-3.88, P  < .001) while no significant concurrent change was observed in mean opinion scores of a non-OUD comparator, diabetes (3.88-3.97, P  = .201)., Conclusions: Results indicate that the workshop was associated with measurable changes in knowledge and attitudinal forms of OUD stigma. With recent policy changes eliminating the X-waiver, healthcare institutions are eager to design curriculum around OUD management and treatment. This study provides a blueprint for an effective curriculum that improves clinician knowledge and reduces stigmatizing attitudes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Introduction: Peer recovery coaches (PRCs) are an important provider group affecting medications for opioid use disorder (MOUD) uptake and retention. However, some PRCs may have experiences and beliefs that do not align with the use of MOUD. This study examines PRCs' perceptions of MOUD and how PRCs' attitudes affect their interactions with clients. The article also explores factors influencing PRCs' attitudes., Methods: The study team conducted semi-structured interviews by phone with PRCs in Michigan (N = 34, July through September 2021). The study asked participants about their opinion of MOUD, how they help clients to make decisions about MOUD, and whether they have encountered negative attitudes toward MOUD in their work. Data analysis was guided by Tracy's (2020) iterative phronetic approach., Results: Nearly all PRCs acknowledged the social stigma surrounding MOUD. PRCs described the stigma toward MOUD as affecting treatment access, utilization, and recovery support. While most PRCs expressed support for many recovery pathways, support for MOUD was contingent on the type of medication and the conditions under which it is used. PRCs often described MOUD as acceptable only in the short-term when paired with psychosocial interventions, after nonpharmacological treatment attempts had failed. PRCs with concerns about MOUD reported sometimes avoiding discussions about MOUD with clients, spreading misinformation about MOUD, and encouraging clients to discontinue treatment. However, many PRCs expressed a desire to support clients' self-determination despite their own biases., Conclusions: Findings highlight a need for education and stigma reduction among PRCs and point to specific areas for intervention. PRCs described deeply engrained beliefs about MOUD rooted in their own treatment histories and recovery practices. Provision of high-quality training and supervision to shift attitudes among PRCs will be key to increasing the use of MOUD., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: This study examines factors associated with psychostimulant misuse, including polysubstance use and social factors, among the understudied American Indian/Alaska Native/Native Hawaiian (AI/AN/NH) college student population., Methods: Data were from the 2015 to 2019 American College Health Association-National College Health Assessment IIc (ACHA-NCHA IIc) survey. Multivariable logistic regression models and odds ratios were used to estimate associations between psychostimulant misuse and potential risk and protective factors among AI/AN/NH college students, including licit and illicit substance use, social support, relationship factors, exposure to violence or abuse, mental health symptoms, drug and alcohol education, and sample demographics., Results: Opioid misuse among AI/AN/NH college students significantly increased the odds of using psychostimulants. Specifically, for cocaine use, the adjusted odds ratio (aOR) was 3.17 with a 95% confidence interval (C.I.) of 2.17 to 4.63; for methamphetamine use, the aOR was 38.87 (95% C.I. 19.24-78.52). For amphetamine misuse among non-Tobacco users, the aOR was 5.47 (95% C.I. 3.49-8.55), while among Tobacco users, the aOR was 2.65 (95% C.I. 2.07-3.41). For cocaine and other stimulant misuse, the aOR was 3.64 (95% C.I. 2.30-5.67). Additionally, the use of other types of licit and illicit substances was associated with greater odds of psychostimulant use and misuse. Conversely, factors such as age, living on campus, and residing in parental/guardian housing were linked with lower odds of psychostimulant use and misuse., Conclusion: Substance use prevention and treatment interventions targeting AI/AN/NH college students should address polysubstance use, including the combined use of opioids and psychostimulants. Substance use interventions should not be siloed to focus narrowly on single substances but rather should leverage potential protective factors against substance use, such as promoting supportive campus and family living conditions and other social support networks, in broad efforts to reduce multiple forms of substance use among AI/AN/NH students., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: The rate of infants born with neonatal abstinence syndrome (NAS) increased by more than 500% between 2004 and 2016. Although feeding problems among infants diagnosed with NAS have been documented, the risk of feeding problems among infants diagnosed with NAS has not been estimated., Purpose: This study evaluates the extent to which feeding problems among infants diagnosed with NAS differ from thise in infants without an NAS diagnosis., Methods/search Strategy: A matched retrospective cohort study (2008-2017) of infants diagnosed with NAS in the United States was conducted using hospital admission data from the Cerner Health Facts Database. Multivariable logistic regressions controlling for confounders were used to assess whether an NAS diagnosis is associated with hospital admission due to feeding problems., Findings/results: Infants with NAS were nearly 3 times as likely (OR = 2.81; 95% CI, 2.68-2.95) to have feeding problems compared with infants without NAS after adjusting for infant and hospital characteristics. Lower birth weight, higher infant age, Hispanic ethnicity, and hospital location in the Midwest region were also associated with higher odds of feeding problems. Infants diagnosed with NAS who had feeding problems had slightly lower odds of being offered lactation services than infants without NAS who had feeding problems., Implications for Practice: These findings suggest the need for targeted feeding interventions., Implications for Research: Future research on infants with NAS may build on these findings by assessing the role of maternal factors such as nutrition and substance use to understand how parental characteristics also influence the risk for hospitalization., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 by The National Association of Neonatal Nurses.)

Background: Past research suggests associations between heavy alcohol use and later life dementia. However, little is known about whether opioid use disorder (OUD) and dementia share this association, especially among age groups younger than 65 years old., Objective: Examine the association between OUD and Alzheimer's disease (AD) and dementia., Methods: Electronic health records between 2000 and 2021 for patients age 12 or older were identified in the Cerner Real-World database™. Patients with a prior diagnosis of dementia were excluded. Patients were followed for 1-10 years (grouped by one, three, five, and ten-year follow-up periods) in a matched retrospective cohort study. Cox proportional hazards regressions were used to estimate adjusted hazard ratios (aHRs) of incident AD/dementia stratified by age and follow-up group., Results: A sample of 627,810 individuals with OUD were compared to 646,340 without OUD. Individuals with OUD exhibited 88% higher risk for developing AD/dementia compared to those without OUD (aHR = 1.88, 95% CI 1.74, 2.03) within 1 year follow-up and 211% (aHR = 3.11, 95% CI 2.63, 3.69) within 10 years follow-up. When stratifying by age, younger patients (age 12-44) had a greater disparity in odds of AD/dementia between OUD and non-OUD groups compared with patients older than 65 years., Conclusions: Additional research is needed to understand why an association exists between OUD and AD/dementia, especially among younger populations. The results suggest that cognitive functioning screening programs for younger people diagnosed with OUD may be useful for targeting early identification and intervention for AD/dementia in particularly high risk and marginalized populations.

Background: We examine the characteristics associated with the availability of therapeutic acupuncture in substance use disorder (SUD) treatment facilities in the United States (US)., Methods: This study utilizes data from the 2018 National Survey of Substance Abuse Treatment Services (N-SSATS). Multivariable logistic regression was performed., Results: Only 5.5% ( n  = 814) of all SUD treatment facilities offered acupuncture therapy. Facilities operating an opioid treatment program (OTP) were 1.60 times more likely to offer therapeutic acupuncture than non-OTP facilities. Facilities that offered oral naltrexone pharmacotherapy or buprenorphine with naloxone pharmacotherapy were 1.63 and 1.37 times more likely to offer therapeutic acupuncture, respectively, compared to facilities that did not offer these pharmacotherapies. Federal government facilities were over four times more likely to offer acupuncture than those operated by state governments and had triple the odds of having acupuncture than private nonprofit organizations. Tribal facilities were over five times more likely than state government-operated facilities to offer acupuncture. Facilities located in the Western region of the US were 1.59, 1.39, and 1.30 times more likely than Northeastern, Midwestern, and Southern US regions, respectively, to offer acupuncture therapy., Conclusions: Although complementary and holistic approaches such as acupuncture are accepted adjunct methods to treat persons with SUD, the findings suggest that their utilization in SUD treatment facilities in the US is minimal. Results, however, highlight that facilities operated by tribal and federal governments, those that are located in the Western region of the US, and non-hospital facilities have the highest odds of incorporating therapeutic acupuncture as treatment for SUD., Supplemental data for this article is available online at https://doi.org/10.1080/10550887.2022.2056401 .

Background: Mental health disorders are prevalent among college students in the US. Perceived discrimination is a known risk factor for adverse mental health and is widespread on college campuses., Methods: We estimated the association between perceived discrimination and mental health among US college students using the American College Health Association-National College Health Assessment (ACHA-NCHA), a large national cross-sectional survey of college students., Results: 7.9% of students reported experiences of discrimination, and that discrimination was more common among minority students. Perceived discrimination was associated with 86 excess cases of students reporting being too depressed to function per 1000 students, and 27 excess cases of students reporting seriously considering suicide per 1000 students. Students who experienced discrimination had a 37% increase in the number of mental health symptoms (IRR 1.37 [95% CI 1.35, 1.39], P < .0001) compared to non-discriminated students, and a 94% increase in the number of mental health diagnoses (IRR 1.94 [95% CI 1.89, 1.99], P < .0001). Discrimination was positively associated with all mental health symptoms and diagnoses. This pattern was largely held across sub-analyses by race/ethnicity, gender, and sexual orientation, but with varying magnitudes., Limitations: Inability to distinguish between the forms of discrimination experienced, whether involving gender, sexual orientation, or race/ethnicity., Conclusions: Consequences of perceived discrimination are of clinical relevance for healthcare providers in general and mental health providers in particular. This study confirms the association between perceived discrimination and adverse mental health in college students. Efforts to reduce discrimination and bias in college campuses may improve the mental health of students., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: The rate of drug overdose deaths in the USA has more than tripled since the turn of the century, and rates are disproportionately high among the American Indian/Alaska Native (AI/AN) population. Little is known about the overall historical trends in AI/AN opioid-only and opioid/polysubstance-related mortality. This study will address this gap., Design: This is a retrospective longitudinal ecological study., Setting: US death records from 1999 to 2019 using the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research., Participants: US non-Hispanic AI/AN people age 12 years and older., Measures: The primary outcomes, identified via the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes, included overdose deaths due to (1) opioids only, opioids in combination with any other substance, all-opioid related overdoses; (2) combinations of opioids and alcohol, opioids and methamphetamine, opioids and cocaine, opioids and benzodiazepines; and (3) specific types of opioids., Results: From 1999 to 2019, opioid-only mortality rates increased from 2.8 to 15.8 per 100 000 (p<0.001) for AI/AN women and 4.6 to 25.6 per 100 000 (p<0.001) for AI/AN men. All opioid-related mortality rates increased significantly (p<0.001) from 5.2 to 33.9 per 100 000 AI/AN persons, 3.9 to 26.1 for women and 6.5 to 42.1 for men. AI/AN also exhibited significant increases in mortality rates due to opioids and alcohol, opioids and benzodiazepines, opioids and methamphetamine, and AI/AN men experienced substantial increases in mortality due to opioids and cocaine. Mortality rates by individual opioid types increased significantly over time for heroin, natural and semi-synthetic (prescription), and synthetic opioids (fentanyl/fentanyl analogues) other than methadone., Conclusions: These findings highlight magnification over time in opioid-related deaths and may point to broader systemic factors that may disproportionately affect members of AI/AN communities and drive inequities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Suicide attempt and opioid misuse continue to be major behavioral health challenges among American Indians and Alaska Natives (AI/AN). The aim of the study is to evaluate the mediating and moderating role that social support (SS) plays in their association among AI/AN high-school students in New Mexico (NM)., Methods: An aggregated NM Youth Resiliency and Risk Survey (NM-YRRS, 2009-2019: odd years) dataset was used. Multivariable logistic regression modeling and mediation analysis were conducted while adjusting for confounding variables., Results: Overall, 12.0 and 14.0% of AI/AN students reported opioid misuse and suicide attempt, respectively. The adjusted odds ratio of suicide attempt in students with high SS relative to low SS who misused opioids was 0.43 (p-value = 0.007). The effect of high SS relative to low SS among males who misused opioids was more pronounced (AOR = 0.24, p-value < 0.0001) compared to females (AOR = 0.43, p-value = 0.007). Relative to low SS, high SS was protective for suicide attempt among AI/AN students who misused opioids and attended school in off-reservation (AOR = 0.42, p-value = 0.012) communities, rural communities (AOR = 0.44, p = 0.040), and in communities that are both rural and off-reservation (AOR = 0.39, p = 0.035). Overall, 23.64, and 41.05% of the association between opioid misuse, and suicide attempt was mediated and moderated by SS, respectively. The mediation effect of SS was lowest for rural, on-reservation schools., Conclusion: More resources need to be allocated to rural on-reservation schools to enhance social support. The study highlights key insights into the significant role SS plays in promoting health and mitigating the association between opioid misuse and suicide attempt., (© 2022. The Author(s).)

Background: American Indian and Alaska Native (AI/AN) youth face stark inequities in opioid misuse, social support, and suicide attempt. This study examined trends in these behavioral measures among AI/AN students in New Mexico (NM)., Methods: Using the NM oversampled Youth Resiliency and Risk Survey (NM-YRRS, 2009 - 2019: odd years), prevalence estimates of opioid misuse, social support (SS), and suicide attempt for AI/AN high school students were generated. Trends over time were assessed via linear regression of weighted proportions according to Peter Armitage. Stratified trends by demographics were also employed., Results: While the prevalence of suicide attempt did not change significantly over time, it was consistently higher among females (2011-2019), those who misused opioids, received low social support, had a mother with less than high school education, had a C, D, or F for academic performance, and non-straight students relative to their counterparts. In particular, the prevalence of suicide attempt among AI/AN students who reported opioid misuse in 2009 was significantly higher by 25.4% than their counterparts who did not report opioid misuse (35.8% vs. 10.4%.) A significant decreasing trend over time (2009-2017) was observed for opioid misuse (16.1%↓8.8%, p-value = 0.0033), including when stratifying by sex (males: 15.9%↓9%, p-value = 0.002; females: 16.2%↓8.6%, p-value = 0.012). Youth with high maternal education exhibited significant decline in opioid misuse (13.5%↓6.7%, p-value = 0.019; 2011-2017.) Opioid misuse increased significantly from 2017 to 2019 (8.8%↑12.9%, p-value < 0.0001.) For instance, in 2019 among AI/AN students who reported low social support, opioid misuse was roughly doubled (18.9% vs. 8.5%, p < 0.0001), and suicide attempt was tripled (21.3% vs. 7.0%, p < 0.0001) compared to students with high social support., Conclusion: No significant trend was observed for suicide attempt. We observed a significant decreasing trend in opioid misuse between 2009 through 2017 but a significant increase from 2017 to 2019. A higher level of maternal education (college or above), and an A or B school grade performance were protective against both opioid misuse and suicide attempt., (© 2022. The Author(s).)

Aims: To assess whether naloxone prescribing in clinical contexts targeted pain patients most at risk for opioid overdose., Design: A retrospective cohort study using data from the Health Facts Database., Setting: Over 600 United States healthcare facilities., Participants: Three patient groups were followed for 2 years during 2009 to 2017: individuals with shoulder or long bone fractures (n = 252 424), chronic pain syndrome (CPS) (n = 76 141), or non-traumatic low back pain (n = 792 956) who received an opioid prescription. Groups were chosen based on previous work., Measurements: The outcome was opioid overdose identified by International Classification of Diseases codes (ICDs) and the primary predictor was number of naloxone prescriptions identified by National Drug Codes (NDCs)., Findings: Opioid overdoses occurred among 0.16% of fracture patients (average follow-up time to overdose [AFU] = 240 days), 1.28% of CPS patients (AFU = 244 days), and 0.30% low back pain patients (AFU = 264 days). A total of 58 083 bone fracture patients received naloxone prescriptions, and naloxone prescription was associated with subsequent opioid overdose (hazard ratio [HR] = 1.87, 95% CI = 1.68-2.09), and number of subsequent overdoses (incidence rate ratio [IRR] = 1.89, 95% CI = 1.69-2.12). A total of 19 529 CPS patients received naloxone prescriptions, and naloxone prescription was associated with subsequent opioid overdose (HR = 1.69, 95% CI = 1.61-1.78) and number of subsequent overdoses (IRR = 1.74, 95% CI = 1.67-1.83). A total of 110 608 low back pain patients received naloxone prescriptions, and naloxone prescription was associated with subsequent opioid overdose (HR = 1.33, 95% CI = 1.27-1.40) and number of subsequent overdoses (IRR = 1.35, 95% CI = 1.29-1.41)., Conclusions: Receiving a naloxone prescription appears to be associated with increased risk of subsequent opioid overdose among patients with acute and chronic pain, suggesting prescribers often identify patients most in need of naloxone., (© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Discrimination has been associated with adverse health behaviors and outcomes, including substance use. Higher rates of substance use are reported among some marginalized groups, such as lesbian, gay, and bisexual populations, and have been partially attributed to discrimination. This study uses 2015-2019 National College Health Assessment data to determine whether college students reporting discrimination due to sexual orientation, race/ethnicity, gender, or age report greater substance use than their peers who do not report such experiences. Additionally, we assess exploratory questions regarding whether substance choices differ among students who reported facing discrimination. Over time, about 8.0% of students reported experiencing discrimination in the past year. After applying inverse probability treatment weights (IPTWs), exposure to discrimination was associated with an excess of 44 cases of marijuana use per 1000 students, an excess of 39 cases of alcohol use per 1000 students, and an excess of 11 cases of prescription painkiller use per 1000 students. Multivariable logistic regression models with IPTW demonstrated that students who experienced discrimination were more than twice as likely to use inhalants and methamphetamine. These students were also significantly more likely to use other drugs, including opiates, non-prescribed painkillers, marijuana, alcohol, hallucinogens, cocaine, and cigarettes; however, the differences with peers were smaller in magnitude. Students who experienced discrimination did not differ from peers who reported non-prescribed antidepressants use and were significantly less likely to use e-cigarettes and smokeless tobacco. Associations between discrimination and substance use vary by race, gender, sexual orientation, and age. These findings indicate that discrimination has significant associations with many kinds of substance use; however, the magnitude varies by substance type. More institutional efforts to address sources of discrimination affecting college students are needed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to investigate inequities in substance use disorder (SUD) diagnosis, opioid misuse, marijuana misuse, SUD treatment utilization, and utilization of university mental health services among sexual and gender minority (SGM) American Indian, Alaska Native, and Native Hawaiian (AI/AN/NH) college students., Methods: Data consisting of 8,103 AI/AN/NH students' responses to the American College Health Association's National College Health Assessment survey from fall 2015 through spring 2019 were utilized for this study. Multivariable logistic regression models were used to compare the odds of SUD diagnosis, opioid misuse, and marijuana misuse in SGM AI/AN/NH students to cisgender, heterosexual peers. Unadjusted odds of SUD treatment utilization and utilization of university mental health services were also evaluated., Results: Compared to cisgender females, transgender (aOR = 4.43, 95% CI = 2.67-7.34) and gender diverse (aOR = 2.86, 95% CI = 1.61-5.07) students had significantly higher odds of SUD diagnosis. Similarly, significantly higher odds of SUD diagnosis were observed among sexual minorities, including gay/lesbian (aOR = 2.95, 95% CI = 1.71-5.09) and bisexual (aOR = 1.97, 95% CI = 1.30-2.99) students compared to heterosexual peers. Sexual minority students had significantly higher odds of utilizing university mental health services (uOR = 2.43, 95% CI = 1.22-4.84) than heterosexual peers. Odds of opioid misuse and marijuana misuse were also significantly increased among sexual minority students., Conclusions: AI/AN/NH college students who identify as SGM have higher odds of SUD diagnosis, opioid misuse, and marijuana misuse than their cisgender, heterosexual peers. These findings highlight the need to consider tailored programming for SGM AI/AN/NH students in substance use prevention and intervention efforts in U.S. college settings.

Background: Provider attitudes can be a powerful reinforcer of stigma toward medication for opioid use disorder (MOUD). This study examines attitudes toward MOUD among substance use treatment providers and identifies personal and professional characteristics associated with more positive attitudes. Methods: Treatment providers (N = 570) working at publicly-funded substance use programs in Michigan self-administered a web-based survey (November 2020 through July 2021), reporting their socio-demographics, professional experience, and attitudes toward MOUD. Linear regression was used to identify factors associated with general attitudes toward MOUD and three logistic regression models were calculated to identify factors associated with perceptions of each medication. Results: Half of providers considered methadone an effective treatment (53.0%); 62.9% considered buprenorphine effective, and 70.3% considered naltrexone effective. Receipt of training (B = 1.433, p = .009) and serving pregnant women or women with children (B = 1.662, p < .001) were associated with more positive attitudes toward MOUD. Providers with advanced degrees were more likely to consider methadone (OR = 2.264, p = .006), buprenorphine (OR = 2.192, p = .009), and naltrexone (OR = 2.310, p = .011) effective. Rural providers were more likely to consider naltrexone effective (OR = 2.708, p = .003). Providers working with criminal legal populations were more likely to consider buprenorphine (OR = 2.948, p = .041) and naltrexone (OR = 4.108, p = .010) effective, but not methadone. Conclusion: Treatment providers' attitudes remain poorly aligned with the evidence base. Increased efforts are needed to address attitudes toward MOUD among the specialized treatment workforce.

Background: The loosening of U.S. methadone regulations during the COVID-19 pandemic expanded calls for methadone reform. This study examines professional perceptions of methadone take-home dose regulation before and during the COVID-19 pandemic to understand responses to varied methadone distribution policies., Methods: Fifty-nine substance use disorder treatment professionals were interviewed between 2017 and 2020 in-person or over video call. An inductive iterative coding process was used to analyze the data. Constructivist grounded theory guided the collection and analysis of in-depth interviews., Results: Treatment professionals expressed mixed views toward methadone take-home regulations. Participants justified regulation using several arguments: 1) patient care benefitting from supervision, 2) attributing improved patient safety to take-home regulation, 3) fearing liability for methadone-related harms, and 4) relying on buprenorphine as an "escape hatch" for patients who cannot manage MMT policies. Other professionals suggested partial deregulation, while others strongly opposed pre-pandemic take-home regulation, explaining such regulations impede medication access and hinder patient-centered care. Some professionals supported the COVID-19 policy changes and saw these as a test run for broader deregulation, while others framed the changes as temporary and cautiously applied deregulation to their services, at times revoking looser rules for patients they perceived as nonadherent., Conclusion: Treatment professionals working in a range of modalities, including opioid treatment programs, expressed hesitation toward expanded take-home methadone access. While some participants also supported forms of deregulation, post-pandemic efforts to extend looser methadone distribution policies will have to address apprehensive professionals if such policy changes are to be meaningfully adopted in community services., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Naltrexone, a medication for addiction treatment (MAT), is an FDA-approved medication recommended for the treatment of alcohol use disorder (AUD). Despite the high prevalence of AUD and efficacy of naltrexone, only a small percentage of individuals with AUD receive treatment., Objectives: To identify trends for the prescription of naltrexone in AUD admissions in substance use treatment centers across the U.S., Methods: Data from the 2000-2018 U.S. Treatment Episode Data Set: Admissions (TEDS-A) were used in temporal trend analysis of naltrexone prescription in admissions that only used alcohol. Data from the 2019 National Survey of Substance Abuse Treatment Services (N-SSATS) were also used to characterize medication use among AUD clients across different treatment service settings., Results: Treatment of AUD with naltrexone was 0.49% in 2000 and tripled from 0.53% in 2015 to 1.64% in 2018 in AUD admissions ( p < 0.0001 for the Cochran-Armitage trend test). Women, middle-aged adults, and admissions for clients living in the Northeast U.S. were more likely to be prescribed naltrexone than their respective counterparts, as were admissions with prior treatment episodes and referrals through alcohol/drug use care providers, who paid for treatment primarily through private insurance, used alcohol daily in the month prior to admission, and waited 1-7 days to enter treatment. Naltrexone was more commonly prescribed by AUD admissions compared to acamprosate and disulfiram and was more frequently prescribed in residential and outpatient services as opposed to hospital inpatient services., Conclusions: Naltrexone remains underutilized for AUD, and factors that influence prescription of medication are multifaceted. This study may contribute to the creation of effective interventions aimed at reducing naltrexone disparities for AUD.

Gamma -amino butyric acid (GABA) is marketed in the U.S. as a dietary supplement. USP conducted a comprehensive safety evaluation of GABA by assessing clinical studies, adverse event information, and toxicology data. Clinical studies investigated the effect of pure GABA as a dietary supplement or as a natural constituent of fermented milk or soy matrices. Data showed no serious adverse events associated with GABA at intakes up to 18 g/d for 4 days and in longer studies at intakes of 120 mg/d for 12 weeks. Some studies showed that GABA was associated with a transient and moderate drop in blood pressure (<10% change). No studies were available on effects of GABA during pregnancy and lactation, and no case reports or spontaneous adverse events associated with GABA were found. Chronic administration of GABA to rats and dogs at doses up to 1 g/kg/day showed no signs of toxicity. Because some studies showed that GABA was associated with decreases in blood pressure, it is conceivable that concurrent use of GABA with anti-hypertensive medications could increase risk of hypotension. Caution is advised for pregnant and lactating women since GABA can affect neurotransmitters and the endocrine system, i.e., increases in growth hormone and prolactin levels.

Background: Both opioid use and COVID-19 affect respiratory and pulmonary health, potentially putting individuals with opioid use disorders (OUD) at risk for complications from COVID-19. We examine the relationship between OUD and subsequent hospitalization, length of stay, risk for invasive ventilator dependence (IVD), and COVID-19 mortality., Methods: Multivariable logistic and exponential regression models using electronic health records data from the Cerner COVID-19 De-Identified Data Cohort from January through June 2020., Findings: Out of 52,312 patients with COVID-19, 1.9% ( n =1,013) had an OUD. COVID-19 patients with an OUD had higher odds of hospitalization (aOR=3.44, 95% CI=2.81-4.21), maximum length of stay ( e β ^ =1.16, 95% CI=1.09-1.22), and odds of IVD (aOR=1.26, 95% CI=1.06-1.49) than patients without an OUD, but did not differ with respect to COVID-19 mortality. However, OUD patients under age 45 exhibited greater COVID-19 mortality (aOR=3.23, 95% CI=1.59-6.56) compared to patients under age 45 without an OUD. OUD patients using opioid agonist treatment (OAT) exhibited higher odds of hospitalization (aOR=5.14, 95% CI=2.75-10.60) and higher maximum length of stay ( e β ^ =1.22, 95% CI=1.01-1.48) than patients without OUDs; however, risk for IVD and COVID-19 mortality did not differ. OUD patients using naltrexone had higher odds of hospitalization (aOR=32.19, 95% CI=4.29-4,119.83), higher maximum length of stay ( e β ^ =1.59, 95% CI=1.06-2.38), and higher odds of IVD (aOR=3.15, 95% CI=1.04-9.51) than patients without OUDs, but mortality did not differ. OUD patients who did not use treatment medication had higher odds of hospitalization (aOR=4.05, 95% CI=3.32-4.98), higher maximum length of stay ( e β ^ =1.14, 95% CI=1.08-1.21), and higher odds of IVD (aOR=1.25, 95% CI=1.04-1.50) and COVID-19 mortality (aOR=1.31, 95% CI=1.07-1.61) than patients without OUDs., Interpretation: This study suggests people with OUD and COVID-19 often require higher levels of care, and OUD patients who are younger or not using medication treatment for OUDs are particularly vulnerable to death due to COVID-19., Competing Interests: Dr. Porucznik reports personal fees from McKesson Corporation, outside the submitted work. All other authors declare no competing interests., (© 2021 The Author(s).)

Background: The spread of the COVID-19 pandemic throughout the world presents an unprecedented challenge to public health inequities. People who use opioids may be a vulnerable group disproportionately impacted by the current pandemic, however, the limited prior research in this area makes it unclear whether COVID-19 and opioid use outcomes may be related, and whether other environmental and socioeconomic factors might play a role in explaining COVID-19 mortality. The objective of this study is to evaluate the association between opioid-related mortality and COVID-19 mortality across U.S. counties., Methods: Data from 3142 counties across the U.S. were used to model the cumulative count of deaths due to COVID-19 up to June 2, 2020. A multivariable negative-binomial regression model was employed to evaluate the adjusted COVID-19 mortality rate ratios (aMRR)., Results: After controlling for covariates, counties with higher rates of opioid-related mortality per 100,000 persons were found to be significantly associated with higher rates of COVID-19 mortality (aMRR: 1.0134; 95% CI [1.0054, 1.0214]; P = 0.001). Counties with higher average daily Particulate Matter (PM2.5) exposure also saw significantly higher rates of COVID-19 mortality. Analyses revealed rural counties, counties with higher percentages of non-Hispanic whites, and counties with increased average maximum temperatures are significantly associated with lower mortality rates from COVID-19., Conclusions: This study indicates need for public health efforts in hard hit COVID-19 regions to also focus prevention efforts on overdose risk among people who use opioids. Future studies using individual-level data are needed to allow for detailed inferences.

Background: Despite declining overall rates of opioid misuse among college students, racial and ethnic differences in percentage and correlates of opioid misuse among student populations remains unclear. This study seeks to estimate percentages of opioid misuse among American Indian, Alaska Native, and Native Hawaiian (AI/AN/NH) college students and determine whether problems in social bonds affect AI/AN/NH opioid misuse., Methods: Guided by social relationship factors associated with substance use in the Social Development Model, we used 2015-2019 data from the American College Health Association-National College Health Assessment survey in multivariable logistic regression models to examine the role of social bonds with peers and family in opioid misuse (prescription and non-prescription) among AI/AN/NH college students across the U.S., Results: The percentage of opioid misuse was highest among AI/AN/NH college students (7.12 %) relative to other race/ethnicity groups. AI/AN/NH college students who reported experiencing loneliness (aOR: 1.68; 95 % CI 1.33-2.12; P < .0001), difficult social relationships (aOR: 1.27; 95 % CI 1.04-1.55; P = 0.0196), family problems (aOR: 1.32; 95 % CI 1.07-1.63; P = 0.0097), and intimate partner violence (aOR: 1.92; 95 % CI 1.56-2.36; P < .0001) were significantly more likely to misuse opioids than students who did not report experiencing these relationship problems., Conclusions: Relationship problems with peers and family increase AI/AN/NH college student risk for opioid misuse, indicating opportunities for colleges to support programs addressing healthy social relationships as a means to reduce opioid misuse among AI/AN/NH students., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Medications for opioid use disorder (MOUD) are evidence-based treatments, yet can be controversial among some populations. This study provides a systematic review of prejudice and discrimination toward MOUD, a form of "intervention stigma," or stigma associated with a particular medical treatment., A systematic search strategy was used in PsychInfo and PubMed to identify studies published between 1998 and 2018. Studies that empirically examined stigma toward MOUD were included if the manuscript was of moderate or high quality. Studies were analyzed using thematic synthesis., The search yielded 972 studies, of which 28 were included. Most studies utilized qualitative methods to examine intervention stigma toward methadone or buprenorphine, with one including naltrexone. Studies demonstrated that intervention stigma among healthcare providers was influenced by lack of training and abstinent treatment preferences. Providers equated MOUD with illicit substance use and at times refused to care for MOUD patients. Stigma among peer patients seeking treatment was also influenced by abstinent treatment preferences, and among the general public stigma was influenced by lack of MOUD knowledge. Intervention stigma was also driven at the policy level by high regulation of methadone, which fueled diversion and hindered social functioning among patients. Few studies indicated how to reduce intervention stigma toward MOUD., Intervention stigma affects both provision and perceptions of methadone and buprenorphine, decreasing access and utilization of MOUD. Future research should further develop and test MOUD stigma reduction interventions in a variety of social contexts to improve access to care and reduce patient barriers.

Low-income U.S. patients with co-occurring behavioral and physical health conditions often struggle to obtain high-quality health care. The health and sociocultural resources of such "complex" patients are misaligned with expectations in most medical settings, which ask patients to mobilize forms of these assets common among healthier and wealthier populations. Thus, complex patients encounter barriers to engagement with their health behaviors and health care providers, resulting in poor outcomes. But this outcome is not inevitable. This study uses in-depth interviews with two interprofessional primary care teams and surveys of all six teams in a complex patient program to examine strategies for improving patient engagement. Five primary care team strategies are identified. While team member burnout was a common byproduct, professional support offered by the team structure reduced this effect. Team perspectives offer insight into mechanisms of improvement and the professional burdens and benefits of efforts to counter health care marginalization among complex patients.

Background : Research indicates U.S. racial and ethnic minority patients are prescribed opioids for pain less often than non-Hispanic Whites. Racial inequities are strongest for pain conditions with uncertain prognosis (e.g., chronic pain syndrome) compared to acute pain with defined duration (e.g., fractures). As naloxone, an opioid overdose reversal drug, becomes more popular among prescribers in clinical contexts, it is unclear whether racial inequities also extend to naloxone prescriptions. Methods : Patients diagnosed with bone fracture ( n  = 551,103) or chronic pain syndrome [CPS] ( n  = 173,341) were identified using ICD-9 and ICD-10 codes in electronic health records from the Health Facts® Database. Logistic regressions were used to determine whether the likelihood of receiving a prescription for opioids or a co-prescription for opioids and naloxone differ by patient race/ethnicity, which included African American, Native American, Non-Hispanic White, Asian/Pacific Islander, Hispanic, and "other" categories. Results : Multiple logistic regressions show naloxone prescriptions do not consistently mirror trends in opioid prescriptions when broken down by patient race/ethnicity and diagnosis. Patients of color with bone fracture or CPS are largely less likely to receive prescriptions for outpatient opioid analgesics than their non-Hispanic White counterparts. Among bone fracture patients prescribed opioids, African Americans and patients of "other" race/ethnicity are also significantly less likely to receive naloxone prescriptions. However, Native American and Hispanic CPS patients prescribed opioids are more likely to get naloxone prescriptions despite being less likely to get opioid prescriptions. And while Native American and Asian/Pacific Islander fracture patients and "other" race/ethnicity CPS patients are less likely to receive an opioid prescription than non-Hispanic Whites, there is no difference from non-Hispanic Whites in their likelihood of receiving a naloxone prescription. Conclusions : Among patients prescribed opioids, naloxone prescriptions vary by patient race/ethnicity and by health condition, indicating the need for efforts to assure equitable diffusion of this harm reduction intervention.

Methadone and buprenorphine are drugs used to treat opioid use disorders, and are labeled the "gold standard" of treatment by the National Institutes of Health. Yet associating with these forms of medication-assisted treatment (MAT) subjects individuals to stigma from healthcare personnel both within and outside addiction treatment communities. This study uses the case of MAT to propose a new category of stigma: "intervention stigma." Unlike "condition stigmas" that mark individuals due to diagnosis, intervention stigma marks patients and health professionals due to involvement with a medical treatment or other form of intervention. In-depth interviews with 47 addiction treatment professionals explore how individuals working in MAT experience discrimination and prejudice from other healthcare professionals, especially abstinent treatment professionals who disagree with the use of medications to treat opioid use disorders. This discrimination and prejudice stems at times from stigma toward addiction diagnoses, and at other times toward unique features of MAT itself. The experiences of addiction treatment professionals illustrate how medical interventions can mark patients and professionals in ways that affect patient care, and thus must be added to the scope of destigmatization efforts operating in the health sector., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Elicit patients' perceptions of factors that facilitate their engagement in care METHODS: In-depth interviews with 20 adult Medicaid patients who had complex health problems, frequent hospitalizations/emergency department use, and who were enrolled in an intensive, team-based care program designed to address medical, behavioral, and social needs., Results: Prior to engaging in the program, participants described weak relationships with primary care providers, frequent hospitalizations and emergency visits, poor adherence to medications and severe social barriers to care. After participating in the program, participants identified key factors that enabled them to develop trust and engage with care including: availability for extended intensive interactions, a non-judgmental approach, addressing patients' material needs, and providing social contact for isolated patients. After developing relationships with their care team, participants described changes such as sustained interactions with their primary care team and incremental improvements in health behaviors., Conclusion: These findings illuminate factors promoting "contingent engagement" for low socio-economic status patients with complex health problems, which allow them to become proactive in ways commensurate with their circumstances, and offers insights for designing interventions to improve patient outcomes., Practice Implications: For these patients, engagement is contingent on healthcare providers' efforts to develop trust and address patients' material needs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Medicare provides access to chronic outpatient dialysis for most U.S. patients diagnosed with end-stage renal disease. However, many new and/or undocumented immigrants do not qualify due to lawful presence and work credit requirements. Medicare-ineligible dialysis patients often wait until their health is poor enough for admission to emergency room dialysis. We use University of New Mexico Hospital chart data from 2013-2016 for a case-control study measuring the likelihood of being admitted to an emergency room for dialysis among patients who use interpreters, which is employed as a proxy for new and undocumented immigrants, compared with other patients. We find Hispanic patients who use an interpreter are significantly more likely to be admitted to emergency rooms for dialysis compared with patients who did not use an interpreter. This study highlights the need for national, state, and local policies to address this inefficient and inequitable healthcare pattern resulting in unnecessary costs and suffering.

Communities struggling with access to healthcare in the U.S. are often considered to be disadvantaged and lacking in resources. Yet, these communities develop and nurture valuable strategies for healthcare access that are underrecognized by health scholars. Combining medical sociology and critical race theory perspectives on cultural capital, this paper examines the health-relevant cultural resources, or Cultural Health Capital, in South Texas Mexican American border communities. Ethnographic data collected during 2011-2013 in Cameron and Hidalgo counties on the U.S.-Mexico border provide empirical evidence for expanding existing notions of health-relevant cultural capital. These Mexican American communities use a range of cultural resources to manage healthcare exclusion and negotiate care in alternative healthcare spaces like community clinics, flea markets and Mexican pharmacies. Navigational, social, familial, and linguistic skills and knowledge are used to access doctors and prescription drugs in these spaces despite social barriers to mainstream healthcare (e.g. cost, English language skills, etc.). Cultural capital used in marginalized communities to navigate limited healthcare options may not always fully counteract healthcare exclusion. Nevertheless, recognizing the cultural resources used in Mexican American communities to facilitate healthcare challenges deficit views and yields important findings for policymakers, healthcare providers, and advocates seeking to capitalize on community resources to improve healthcare access., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Exposures to complex mixtures of metals in the workplace or environment are more likely to occur than exposures to a single metal alone. The evidence shows that exposures to complex metal mixtures can enhance the risk of cancer in certain human populations. The findings of several studies have suggested, however, that certain metal-metal interactions can inhibit carcinogenic activity. The mechanisms of metal-metal interactions in human carcinogenesis are relatively unknown. Metals represent a highly diverse group of agents: each metal can act through different mechanisms and in one or more steps of the carcinogenic process. Some potential mechanisms may involve direct reactions of the metal with DNA or indirect mechanisms that include modification of DNA repair, DNA methylation status, and metabolic processes involved in DNA replication and expression. Lipid peroxidation and the generation of free radicals induced by certain metals can affect DNA integrity. This review will address the role of metals in carcinogenesis and how concomitant exposure to metal mixtures can influence cancer induction. The most current mechanistic data regarding metal interactions and its implications in human carcinogenesis will be discussed. Furthermore, research gaps will be identified to provide data that will improve risk assessments for complex metal mixtures encountered in the workplace and environment.

Arsenite and cadmium are two potent nephrotoxicants and common Superfund site elements. These elements are included among the stress protein inducers, but information regarding relationships between toxicity produced by combinations of these agents to the stress protein response is lacking. In this study, the immortalized cell lines normal rat kidney NRK-52E and human kidney HK-2 were exposed in vitro to arsenite (As(3+)), cadmium (Cd(2+)), or to equimolar As(3+) plus Cd(2+) mixture combinations for 3 and 5 h over a concentration range of 0.1-100 microM. After a 12-h recovery period, cultured cells were then evaluated for expression of the 60, 70, and 90 kDa major stress protein families. Results indicated that expression of stress proteins varied depending on the species of kidney cells exposed, the exposure concentrations, and the length of exposure to each element on an individual basis and for combined mixtures. For the HK-2 kidney cell line, increased levels of the 70 kDa stress protein was observed for single and combined element exposures whereas there was no change or a decrease of stress proteins 60 and 90 kDa. Increased 70 kDa expression was observed for 10-microM doses of single elements and for a lower dose of 1 microM of the As plus Cd mixture at 3- and 5-h exposures. NRK-52 kidney cells exposed to equivalent doses of As(3+) and Cd(2+) alone or in combination showed increased levels of all stress proteins 60, 70, and 90 kDa. This increase was seen for 10 microM of the As plus Cd mixture at 3 h whereas for single element exposures, increased stress protein levels were generally observed for the 100-microM doses. At 5 h- exposure, 60 and 90 kDa levels increased for 10 microM of Cd(2+) and 60 kDa levels increased for 1 microM of As(3+). However, exposures to 10 microM of the As plus Cd mixture decreased 60 kDa protein expression to control levels at 5 h. For both kidney cell lines, there was a decrease in the stress protein expression levels for all three stress protein families for 100-microM doses of the mixture combination for 3- and 5-h exposures. These data indicate a dose- and combination-related correlation between depression of the stress protein response and the onset of overt cellular toxicity and/or cell death. The threshold for these changes was cell line specific., (Copyright 2002 Wiley Periodicals, Inc.)

The common environmental pollutants arsenic, lead, and cadmium are each known to induce chronic renal disease and the molecular mechanisms of such toxic events are being clarified. Nephrotoxicity of these metals is due to the fact that urinary elimination is a main route of excretion, and the proximal tubules are especially sensitive due to their high reabsorptive activity. Renal pathological effects of these metals vary with the chemical form of the metal, the dose, and whether the exposure is acute or chronic in nature. The few isolated studies of combined metal exposures indicate that these pathological effects may be altered due to unknown interactions of these metals within the kidney. Biological factors within the cell such as metal binding proteins and inclusion bodies may also influence metal-metal interactions. Further research is needed to specify the parameters or criteria by which metal interactions is to be assessed for unique biological response patterns to aid in the risk assessment analysis of environmental and occupational metal exposures.