Prior emergency medical services utilization is a risk factor for in-hospital death among patients with substance misuse: a retrospective cohort study.

BACKGROUND: Substance misuse poses a significant public health challenge, characterized by premature morbidity and mortality, and heightened healthcare utilization. While studies have demonstrated that previous hospitalizations and emergency department visits are associated with increased mortality in patients with substance misuse, it is unknown whether prior utilization of emergency medical service (EMS) is similarly associated with poor outcomes among this population. The objective of this study is to determine the association between EMS utilization in the 30 days before a hospitalization or emergency department visit and in-hospital outcomes among patients with substance misuse. METHODS: We conducted a retrospective analysis of adult emergency department visits and hospitalizations (referred to as a hospital encounter) between 2017 and 2021 within the Substance Misuse Data Commons, which maintains electronic health records from substance misuse patients seen at two University of Wisconsin hospitals, linked with state agency, claims, and socioeconomic datasets. Using regression models, we examined the association between EMS use and the outcomes of in-hospital death, hospital length of stay, intensive care unit (ICU) admission, and critical illness events, defined by invasive mechanical ventilation or vasoactive drug administration. Models were adjusted for age, comorbidities, initial severity of illness, substance misuse type, and socioeconomic status. RESULTS: Among 19,402 encounters, individuals with substance misuse who had at least one EMS incident within 30 days of a hospital encounter experienced a higher likelihood of in-hospital mortality (OR 1.52, 95% CI [1.05 - 2.14]) compared to those without prior EMS use, after adjusting for confounders. Using EMS in the 30 days prior to an encounter was associated with a small increase in hospital length of stay but was not associated with ICU admission or critical illness events. CONCLUSIONS: Individuals with substance misuse who have used EMS in the month preceding a hospital encounter are at an increased risk of in-hospital mortality. Enhanced monitoring of EMS users in this population could improve overall patient outcomes.

Opioid-Related Emergency Department Visits Before and During COVID-19: Association with Community-Level Factors.

Background: The purpose of the study was to investigate the relationship between community-level variables and emergency department (ED) visit rates before and during COVID-19. The focus was on opioid-related ED visits. Despite large declines in overall ED visits during COVID-19, opioid-related visits increased. While visits for avoidable conditions decreased, the opposite was true for opioid-related visits. Methods: We combined data from Florida EDs with community-level variables from the 2020 American Community Survey. The outcome measures of the study were quarterly ZIP code tabulation-area-level ED visit rates for opioid-related ED visits as well as visit rates for all other causes. Associations with opioid-related visit rates were estimated before and during COVID-19. Results: The associations between community-level variables and opioid-related visit rates did not match those found when analyzing overall ED visit rates. The increase in opioid-related visits during COVID-19 was not unique to or more prevalent in areas with a larger percentage of racial/ethnic minority populations. However, socioeconomic status was important, as areas with higher unemployment, lower income, lower home ownership, and higher uninsured had higher overall ED visit rates and opioid visit rates during the pandemic. In addition, the negative association with income increased during the pandemic. Conclusion: These results suggest socioeconomic status should be the focus of prevention and treatment efforts to reduce opioid-related visits in future pandemics. Healthcare organizations can use these results to target their prevention and treatment efforts during future pandemics.

An Observational Study of a Digital Substance Use and Recovery Program.

OBJECTIVE: Digital substance use treatment programs present an opportunity to provide nonresidential care for people with problematic substance use. In June 2021, the provincial government in Ontario provided free access to Breaking Free Online (BFO), a digital behavioral change program for people with substance use disorders. METHODS: An observational study was conducted with retrospective data to characterize clients' use and engagement patterns in BFO and examine changes in self-reported outcomes. RESULTS: In total, 6,370 individuals registered for BFO between June 2021 and October 2022, of whom 3,650 completed the intake assessment. Most of these clients were self-referred (64%), with 37% having been referred by health service providers. More than one-half of the clients (52%) resided in Ontario West or East regions. Support for addressing problematic alcohol use was the most requested program (40%). By October 2022, about 44% of the clients had completed between one and four of 12 program strategies. Analysis revealed significant changes in pre-post scores across four validated scales (p<0.001), indicating a decrease in anxiety and depression, an increase in quality of life, an improvement in recovery progression, and a decrease in severity of symptoms associated with substance use disorders. CONCLUSIONS: BFO clients with higher completion rates had the most improvement across the scales used; however, clients with lower and medium completion rates also had improvements. Because of the shame and stigma associated with substance use, digital supports with low barriers to entry can help support the autonomy, privacy, and preferences of individuals seeking help for problematic substance use.

Predictors of alcohol and other drug treatment completion among young people accessing residential and community-based treatment: A retrospective analysis of routinely collected service data.

BACKGROUND AND AIMS: Young people accessing alcohol and other drug (AOD) treatment experience high rates of treatment disengagement, contributing to poorer outcomes. To improve outcomes, it is important to identify factors associated with treatment retention. This study measured the relationships between client characteristics, treatment characteristics, clinical severity measures and completion of treatment among young people. DESIGN, SETTING AND PARTICIPANTS: This study was a retrospective analysis of routinely collected data set in residential- and community-based AOD services in New South Wales, Australia. Routinely collected data from the Network of Alcohol and Other Drug Agencies' (NADA) database were used. Included individuals were aged 10-24 years and accessed treatment between 2012 and 2023 (n = 17 474). MEASUREMENTS: Variables included client-related characteristics, service characteristics and baseline measures of clinical severity [Kessler-10 (K10), EUROHIS-QoL, severity of dependence scale (SDS)]. Multivariable binary logistic regression models assessed the relationships between these characteristics and treatment completion. FINDINGS: Rates of treatment completion were highest among adolescents in community-based treatment (57%) and lowest among young adults in residential treatment (35%). Polysubstance use was negatively associated with treatment completion among adolescents [adjusted odds ratio (adjOR) = 0.71, P < 0.001] and adults (adjOR = 0.70, P < 0.001) in community-based treatment, and adolescents in residential treatment (adjOR = 0.62, P = 0.006), as was housing insecurity (adolescents in community treatment, adjOR = 0.61, P = 0.001; adults in community treatment, adjOR = 0.77, P = 0.002; adolescents in residential treatment, adjOR = 0.42, P = 0.005). Attending youth-specific services was associated with higher treatment completion rates among adults in community-based (adjOR = 1.81, P < 0.001) and residential treatment (adjOR = 1.72, P < 0.001). Varying correlates of treatment completion were identified throughout treatment groups, reflecting the differences in population and/or needs across contexts. CONCLUSIONS: In New South Wales, Australia, fewer than half of young people accessing alcohol and other drug treatment between 2012 and 2023 completed treatment, and completion rates were lower among those facing barriers such as polysubstance use and housing insecurity.

Clinical detoxification of bromazolam using diazepam: a case report.

An increasing number of new psychoactive substances (NPS), such as designer benzodiazepines, are becoming available on the recreational drug market. These are new unregistered substances and thereby an attempt to evade legislation. Often there is very limited clinical information available regarding these NPS, which could result in undesirable clinical outcomes in the management of intoxications, dependencies and withdrawals following NPS use. In this case report we describe a 23-year-old woman, who was admitted to our residential addiction care facility for the detoxification of the designer benzodiazepine bromazolam. Her daily use of 6 mg bromazolam was converted to 20 mg diazepam. Although we expected a higher dose would have been needed, 20 mg was sufficient and was tapered without complications. This case report demonstrates the safe conversion of 6 mg of bromazolam to 20 mg of diazepam by combining the use of fixed-dose and symptom-triggered-dose regimens. More clinical data is necessary to formulate advisory management for the detoxification of bromazolam and other designer benzodiazepines.

Cannabis and anhedonia: A systematic review.

This paper employs a systematic review to examine the correlation between anhedonia and marijuana use, exploring whether individuals with anhedonia use marijuana as a coping mechanism or if marijuana use plays a role in the onset of anhedonia. The search utilised PubMed and Web of Science databases, following PRISMA guidelines for paper selection. A total of 21 papers were selected to address this inquiry, and assessments were carried out using the Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool. The results revealed that 17 studies exhibited moderate and low risk of bias. The evaluation encompassed a total of 12,427 participants, including both animals and humans. Experimental animal studies focused on exploring the association between cannabidiol (CBD) and anhedonia, while human studies primarily employed observational research, examining various forms of anhedonia in individuals with or without mental disorders such as depression or psychosis. These studies also delved into understanding the effects of anhedonia during adolescence and explored the causal relationship between these concepts. The findings indicate a reciprocal rather than unidirectional relationship, establishing that initial anhedonia predisposes individuals to cannabis use, and subsequent consumption significantly intensifies the anhedonia experienced. Particularly, the studies placed special emphasis on adolescents and individuals with mental disorders.

Systematic review of treatment completion rates and correlates among young people accessing alcohol and other drug treatment.

BACKGROUND AND AIMS: Treatment completion is associated with improved alcohol and other drug (AOD) treatment outcomes. Unfortunately, treatment disengagement is common, particularly among young people. We reviewed and synthesised research on AOD treatment completion and/or early disengagement among young people. METHODS: We conducted a systematic review and meta-analysis of studies reporting on completion rates and/or early disengagement from psychosocial AOD treatment among adolescents and young adults. An overall estimated treatment completion rate was calculated using inverse-variance random effects meta-analysis, and random-effects meta-regression was used to identify between-study level moderators of completion rate. We completed a narrative review summarising literature on early treatment disengagement and within-study level correlates of treatment completion. Study quality was assessed using the EPHPP. RESULTS: Of the 6158 studies screened, we retained 410 for full text review and included 98 studies in the review. Treatment completion rates were reported in 88 studies, and early disengagement rates were reported in 13. The estimated overall treatment completion rate was 59 % (95 % CI=57-61 %), with experimental studies reporting higher rates of completion than observational studies. There was limited evidence for demographic or substance-related correlates of treatment completion. Contingency management was associated with increased completion rates, as was family-based intervention. CONCLUSIONS: Disengagement from AOD treatment among youth populations is common and contributes to poor treatment outcomes. Existing research has yielded little consensus on the factors associated with treatment completion. The use of contingency management strategies and involving family/social supports in treatment were identified as potential avenues for promoting ongoing treatment engagement.

Asynchronous online training increased knowledge, confidence, and intent to screen and treat substance use disorders among primary care clinicians practicing in Texas.

INTRODUCTION: Despite increasing prevalence of substance use disorders (SUD), few patients are diagnosed and treated in primary care settings. This study evaluated changes in knowledge, confidence, and intention to implement screening and brief intervention (SBI) and SUD treatment after clinicians participated in an asynchronous online education course. METHODS: A self-selected sample of primary care clinicians in Texas participated in online SBI and SUD education March 2021-July 2023. Baseline and post-training surveys evaluated changes in knowledge, confidence, and intent to implement SBI and SUD treatment. Changes were compared using paired t-tests. Multivariable linear regression examined factors potentially associated with confidence and intention to implement changes. Clinician feedback regarding the course was included. RESULTS: Of 613 respondents, 50.9% were practicing family medicine clinicians. Knowledge of adolescent screening tools increased from 21.9% to 75.7% (p < 0.001). Knowledge about the number of drinks that define excessive drinking among non-pregnant women increased from 24.5% at baseline to 64.9% (p < 0.001). Clinicians reported lowest confidence in providing opioid use disorder pharmacotherapy, which improved after program participation. Intent to implement SBI and medication for alcohol, nicotine and opioid use disorders increased (p < 0.001) after training. No factors were associated with change in confidence or intention to implement in multivariable models (p > 0.05). Satisfaction was high and nearly 60% reported intention to change their clinical practice because of the program. CONCLUSION: Knowledge, confidence, and intent to implement SBI and SUD treatment increased after completing the online course. Clinician satisfaction was high and demonstrated improved intention to implement SBI and SUD treatment.

Barriers and Facilitators to Using a Clinical Decision Support Tool for Opioid Use Disorder in Primary Care.

PURPOSE: Clinical decision support (CDS) tools are designed to help primary care clinicians (PCCs) implement evidence-based guidelines for chronic disease care. CDS tools may also be helpful for opioid use disorder (OUD), but only if PCCs use them in their regular workflow. This study's purpose was to understand PCC and clinic leader perceptions of barriers to using an OUD-CDS tool in primary care. METHODS: PCCs and leaders (n = 13) from clinics in an integrated health system in which an OUD-CDS tool was implemented participated in semistructured qualitative interviews. Questions aimed to understand whether the CDS tool design, implementation, context, and content were barriers or facilitators to using the OUD-CDS in primary care. Recruitment stopped when thematic saturation was reached. An inductive thematic analysis approach was used to generate overall themes. RESULTS: Five themes emerged: (1) PCCs prefer to minimize conversations about OUD risk and treatment; (2) PCCs are enthusiastic about a CDS tool that addresses a topic of interest but lack interest in treating OUD; (3) contextual barriers in primary care limit PCCs' ability to use CDS to manage OUD; (4) CDS needs to be simple and visible, save time, and add value to care; and (5) CDS has value in identifying and screening patients and facilitating referrals. CONCLUSIONS: This study identified several factors that impact use of an OUD-CDS tool in primary care, including PCC interest in treating OUD, contextual barriers, and CDS design. These results may help others interested in implementing CDS for OUD in primary care.

Client and stakeholder perceptions of a novel, nurse practitioner-led alcohol and other drug ambulatory withdrawal service.

INTRODUCTION: Despite recommendations for ambulatory withdrawal programs appearing in many contemporary alcohol and other drug treatment guidelines, to date there have been few studies exploring such programs from client and service stakeholder perspectives. The aim of this study was to explore both individual and service stakeholder perceptions of a nurse practitioner-led ambulatory withdrawal service on the Gold Coast, Queensland, Australia. METHODS: Data were obtained from three groups: clinicians with knowledge of the service (n = 6); relatives of clients who had used the service (n = 2); and clients who had used the service (n = 10) using a Qualitative Descriptive design. Saldaña's (Saldaña, The coding manual for qualitative researchers. 2013) structural coding framework was used to analyse and code data into themes, with the study reported in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist (Tong et al. Int J Qual Health Care 2017;19:349-57). RESULTS: Participants noted advantages of the nurse practitioner-led ambulatory withdrawal service, including rapid availability of admission to the service and a person-centred approach. Compared with other ambulatory withdrawal options, clients valued the ability to remain in their own environment, however participants suggested greater follow-up after withdrawal, with the potential of a home visiting service for greater client engagement and treatment retention. DISCUSSION AND CONCLUSIONS: Findings provide evidence to suggest that nurse practitioner-led ambulatory withdrawal services are an acceptable option for a proportion of clients who need rapid access to services when they wish to make changes to their alcohol and/or other drug use. Furthermore, they can provide person-centred care for comorbid physical and mental ill health occurring in addition to psychosocial issues associated with alcohol and/or other drug use.

Inpatient case characteristics of SGLT2 inhibitor-associated diabetic ketoacidosis: a retrospective study.

OBJECTIVES: Diabetic ketoacidosis (DKA) is a serious complication in patients treated with sodium-glucose co-transporter 2 inhibitors (SGLT2i). The aim of this study was to investigate the relationship between SGLT2i and the risk of DKA, and to identify high-risk groups and characteristics that should be emphasised. METHODS: A retrospective case series study was conducted to collect medical records of inpatients diagnosed with DKA and using SGLT2i before the onset of the disease from September 2022 to September 2023 in a tertiary hospital in Shanghai. Cases that met the inclusion criteria were retrieved through the electronic medical record system. Information was collected to compare the risk of DKA in patients with different characteristics. RESULTS: A total of 21 patients (12 men and 9 women) met the criteria for SGLT2i-associated DKA. The mean diabetes duration was 10.4 years, with 47.6% (10/21) of patients diagnosed with euglycaemic DKA. The drug treatment regimen most commonly used was the combination of SGLT2i and metformin, representing 52.4% (11/21) of cases. The most common clinical symptoms were nausea, vomiting, abdominal pain and malaise. Common predisposing factors were acute infections, acute pancreatitis (predominantly hyperlipidaemic type), dietary inappropriateness, acute cardiovascular and cerebrovascular events and surgery. 71.4% of patients (15/21) had multiple risk factors. CONCLUSION: The use of SGLT2i in diabetic patients is associated with an increased risk of DKA, particularly in the presence of predisposing factors such as infection. Furthermore, long diabetes duration, decreased pancreatic ß-cell function and the combined use of metformin may also contribute to the risk of DKA in patients treated with SGLT2i. The findings of this study provide valuable insights for better identification and management of DKA risks associated with SGLT2i in clinical practice.

The Psychiatrist's Role in Treating Perinatal Opioid Use Disorder and Reducing Maternal Mortality.

Drug overdose is a leading cause of maternal mortality. Psychiatrists can play a critical role in reducing these deaths by delivering effective evidence-based treatments for perinatal opioid use disorder (POUD), including the use of buprenorphine. Medications for POUD (i.e., buprenorphine, methadone) are life-saving treatments, but only half of those who are diagnosed as having POUD will receive this treatment, which can result in an increased risk for return to opioid use, overdose, and death. Psychiatrists are well positioned to prescribe buprenorphine given the Drug Enforcement Administration's (DEA) removal of the requirement to submit a Notice of Intent to prescribe buprenorphine for the treatment of opioid use disorders. Psychiatrists who have a current DEA registration that includes Schedule III authority may now prescribe buprenorphine for opioid use disorders; the training requirements to do so are outlined herein. This article reviews the standard of care for screening, diagnosis, and treatment of POUD, and prescribing buprenorphine for POUD, as well as shared decision-making for medication selection, induction, and maintenance of buprenorphine during pregnancy, labor and delivery, and the postpartum year.

Associations Between a Primary Care-Delivered Alcohol-Related Brief Intervention and Subsequent Opioid-Related Outcomes.

OBJECTIVE: The co-occurrence of unhealthy alcohol use and opioid misuse is high and associated with increased rates of overdose, emergency health care utilization, and death. The current study examined whether receipt of an alcohol-related brief intervention is associated with reduced risk of negative downstream opioid-related outcomes. METHODS: This retrospective cohort study included all VISN-6 Veterans Affairs (VA) patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening results (N=492,748) from 2014 to 2019. Logistic regression was used to examine the association between documentation of an alcohol-related brief intervention and probability of a new 1) opioid prescription, 2) opioid use disorder (OUD) diagnosis, or 3) opioid-related hospitalization in the following year, controlling for demographic and clinical covariates. RESULTS: Of the veterans, 13% (N=63,804) had "positive" AUDIT-C screen results. Of those, 72% (N=46,216) had a documented alcohol-related brief intervention. Within 1 year, 8.5% (N=5,430) had a new opioid prescription, 1.1% (N=698) had a new OUD diagnosis, and 0.8% (N=499) had a new opioid-related hospitalization. In adjusted models, veterans with positive AUDIT-C screen results who did not receive an alcohol-related brief intervention had higher odds of new opioid prescriptions (adjusted odds ratio [OR]=1.10, 95% CI=1.03-1.17) and new OUD diagnoses (adjusted OR=1.19, 95% CI=1.02-1.40), while new opioid-related hospitalizations (adjusted OR=1.19, 95% CI=0.99-1.44) were higher although not statistically significant. Removal of medications for OUD (MOUD) did not impact associations. All outcomes were significantly associated with an alcohol-related brief intervention in unadjusted models. CONCLUSIONS: The VA's standard alcohol-related brief intervention is associated with subsequent lower odds of a new opioid prescription or a new OUD diagnosis. Results suggest a reduction in a cascade of new opioid-related outcomes from prescriptions through hospitalizations.

A qualitative study of experiences with physical activity among people receiving opioid agonist therapy.

BACKGROUND: Physical or mental health comorbidities are common among people with substance use disorders undergoing opioid agonist therapy. As both a preventive and treatment strategy, exercise offers various health benefits for several conditions. Exercise interventions to people with substance use disorders receiving opioid agonist therapy are limited. This study aims to explore experiences with physical activity, perceived barriers, and facilitators among people receiving opioid agonist therapy. METHOD: Fourteen qualitative interviews were conducted with individuals receiving opioid agonist therapy in outpatient clinics in Western Norway. RESULTS: Most were males in the age range 30 to 60 years. Participants had diverse and long-term substance use histories, and most received buprenorphine-based opioid agonist therapy. The identified themes were (1) Physical limitations: Participants experienced health-related problems like breathing difficulties, pain, and reduced physical function. (2) Social dynamics: Social support was essential for participating in physical activities and many argued for group exercises, but some were concerned about the possibility of meeting persons influenced by substances in a group setting, fearing temptations to use substances. (3) Shift in focus: As participants felt the weight of the health burden, their preference for activities shifted from sports aiming for "adrenaline" to a health promoting focus. (4) COVID-19's impact on exercise: because of the pandemic, group activities were suspended, and participants described it as challenging to resume. (5) Implementation preferences in clinics: Not interfering with opioid medication routines was reported to be essential. CONCLUSION: This study offers valuable insights for the development of customized exercise interventions aimed at enhancing the health and well-being of patients undergoing opioid agonist therapy. These findings underscore the significance of addressing social dynamics, overcoming physical limitations, and implementing a practical and effective exercise regimen.

Vaccines as Immunotherapies for Substance Use Disorders.

Substance use disorders (SUD) present a worldwide challenge with few effective therapies except for the relative efficacy of opioid pharmacotherapies, despite limited treatment access. However, the proliferation of illicit fentanyl use initiated a dramatic and cascading epidemic of lethal overdoses. This rise in fentanyl overdoses regenerated an interest in vaccine immunotherapy, which, despite an optimistic start in animal models over the past 50 years, yielded disappointing results in human clinical trials of vaccines against nicotine, stimulants (cocaine and methamphetamine), and opioids. After a brief review of clinical and selected preclinical vaccine studies, the "lessons learned" from the previous vaccine clinical trials are summarized, and then the newest challenge of a vaccine against fentanyl and its analogs is explored. Animal studies have made significant advances in vaccine technology for SUD treatment over the past 50 years, and the resulting anti-fentanyl vaccines show remarkable promise for ending this epidemic of fentanyl deaths.

Harm Reduction for Opioid Use Disorder: Strategies and Outcome Metrics.

Tweet: The authors discuss harm reduction strategies and associated outcome metrics in relation to the ongoing opioid crisis.

Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic.

Alcohol use disorder (AUD) and chronic pain disorders are pervasive, multifaceted medical conditions that often co-occur. However, their comorbidity is often overlooked, despite its prevalence and clinical relevance. Individuals with AUD are more likely to experience chronic pain than the general population. Conversely, individuals with chronic pain commonly alleviate their pain with alcohol, which may escalate into AUD. This narrative review discusses the intricate relationship between AUD and chronic pain. Based on the literature available, the authors present a theoretical model explaining the reciprocal relationship between AUD and chronic pain across alcohol intoxication and withdrawal. They propose that the use of alcohol for analgesia rapidly gives way to acute tolerance, triggering the need for higher levels of alcohol consumption. Attempts at abstinence lead to alcohol withdrawal syndrome and hyperalgesia, increasing the risk of relapse. Chronic neurobiological changes lead to preoccupation with pain and cravings for alcohol, further entrenching both conditions. To stimulate research in this area, the authors review methodologies to improve the assessment of pain in AUD studies, including self-report and psychophysical methods. Further, they discuss pharmacotherapies and psychotherapies that may target both conditions, potentially improving both AUD and chronic pain outcomes simultaneously. Finally, the authors emphasize the need to manage both conditions concurrently, and encourage both the scientific community and clinicians to ensure that these intertwined conditions are not overlooked given their clinical significance.

Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA).

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike and affected the global drug supply over the past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs have posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used to identify AI limits in some cases; however, this approach is limited by the availability of robustly-tested surrogates matching the structural features of NDSRIs, which usually contain a diverse array of functional groups. Furthermore, the absence of a surrogate has resulted in conservative AI limits in some cases, posing practical challenges for impurity control. Therefore, a new framework for determining recommended AI limits was urgently needed. Here, the Carcinogenic Potency Categorization Approach (CPCA) and its supporting scientific rationale are presented. The CPCA is a rapidly-applied structure-activity relationship-based method that assigns a nitrosamine to 1 of 5 categories, each with a corresponding AI limit, reflecting predicted carcinogenic potency. The CPCA considers the number and distribution of α-hydrogens at the N-nitroso center and other activating and deactivating structural features of a nitrosamine that affect the α-hydroxylation metabolic activation pathway of carcinogenesis. The CPCA has been adopted internationally by several drug regulatory authorities as a simplified approach and a starting point to determine recommended AI limits for nitrosamines without the need for compound-specific empirical data.