Geopersonality of Preventable Death in the United States: Anger-Prone States and Opioid Deaths.

BACKGROUND: Opioid overdoses have reached epidemic levels in the United States and have clustered in Northeastern and "Rust Belt" states. Five Factor Model (FFM) personality traits also vary at the state level, with anger-prone traits clustered in the Northeast region. This study tested the hypothesis that state-level anger proneness would be associated with a greater increase in rates of opioid overdose death. METHODS: This was a secondary analysis of state-level data on FFM traits, opioid overdose deaths, and other classes of preventable death. Robust mixed models tested whether change in rates of opioid overdose death from 2008 to 2016 was moderated by state-level anger proneness. RESULTS: State-level anger proneness was significantly associated with greater increases in rates of opioid overdose deaths (B = 1.01, standard error = 0.19, P < .001, 95% confidence interval: 0.63-1.39). The slope of increase in opioid overdose death rates was 380% greater in anger-prone states and held after adjustment for potential confounders such as state-level prevalence of major depressive disorder, number of mental health facilities, and historical patterns of manufacturing decline. A similar pattern was observed between state-level anger proneness and benzodiazepine overdose deaths but was not significant for the latter after adjustment for potential confounders. CONCLUSION: These findings suggest that states characterized as more anger prone have experienced greater increases in opioid overdose deaths.

Medicaid expansion and opioid deaths.

The United States is in the midst of an opioid epidemic, and drug overdose deaths are becoming a leading cause of death. Meanwhile, in 2010, the United States passed comprehensive health care reform providing access to care for millions of individuals who previously lacked care. Part of the new access came from expanding Medicaid, the insurance program for low-income individuals. Expanding Medicaid was optional for states. Those individuals living in expansion states gained prescription drug coverage and hence more access to opioid pain-relievers that are known to be addictive. However, they also gained access to medication-assisted treatment for addiction. This paper uses a difference-in-differences approach and state-level data from 2010 to 2017 to compare opioid death rates in expansion and non-expansion states to determine if Medicaid expansion was a potential cause of rising opioid deaths. We find no evidence that Medicaid expansion is related to opioid deaths.

Nonclinical safety assessment of PF614: A novel TAAP prodrug of oxycodone for chronic pain indication.

PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC50 for PF614 was ≥300 µM. PF614 (0.1 and 10 µM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.

Evolution of the national opioid crisis.

Opioid use disorder (OUD), addiction, and overdose have become a national public health and socioeconomic crisis. This article explores the evolution of substance abuse in the US, specifically OUD.

Health equity-oriented approaches to inform responses to opioid overdoses: a scoping review protocol.

REVIEW QUESTION/OBJECTIVES: The purpose of this scoping review is to systematically identify and describe literature that uses a health equity-oriented (HEO) approach for preventing and reducing the harms of stigma or overdose for people who use illicit drugs or misuse prescription opioids.The question of the review is: What is currently known about the use of an HEO approach for preventing the harms of stigma or overdose when people use illicit or street drugs, or use prescription opioids for other than their intended purposes?Specifically, the review objectives are.

Cardiorespiratory morbidity and mortality of opioid overdose during admission to safety-net hospitals.

STUDY OBJECTIVE: Safety-net hospitals disproportionately care for high-risk patients. Prior work has shown safety-net hospitals to have inferior postoperative outcomes with higher cost and worse patient ratings. We aim to examine the association of hospital safety-net burden with morbidity and mortality in patients with opioid overdose hospital admission. DESIGN: Retrospective cross-sectional analysis using the National Inpatient Sample registry from 2010 to 2014. SETTING: Multi-institutional. PATIENTS: We included 547, 399 patients admitted to a United States hospital with an International Classification of Disease, Ninth Revision, code of opioid overdose. To study the association of hospital safety-net burden on mortality and morbidity, we calculated hospital safety-net burden defined as the percent of Medicaid or uninsured among all admitted patients. Hospitals were categorized into one of three categories: low burden hospitals, medium burden hospitals, and high burden hospitals (i.e., safety-net hospitals). We performed a mixed effects multivariable logistic regression analysis to assess the association of hospital safety-net burden with short-term inpatient outcomes. INTERVENTION: None. MEASUREMENTS: The primary outcomes were inpatient mortality and morbidity. MAIN RESULTS: Compared to MBHs and LBHs, HBHs had a greater proportion of minority patients (i.e., Black, Hispanic, and Native American) and patients with median household income in the lowest quartile (p < 0.001). Among prescription opioid overdose admissions, the odds of inpatient mortality and pulmonary and cardiac morbidity were also not significantly higher between HBHs versus LBHs (p > 0.05). CONCLUSIONS: Safety-net hospital disproportionately care for vulnerable populations, however the odds of poor outcomes were no different in opioid overdose. Safety-net hospitals should have equal access to the funding and resources that allows them to deliver the same standard of care as their counterparts.

Sociodemographic factors, prescription history and opioid overdose deaths: a statewide analysis using linked PDMP and mortality data.

BACKGROUND: Opioid overdose deaths have continued to rise in Tennessee (TN) with fentanyl emerging as a major contributor. Current data are needed to identify at-risk populations to guide prevention strategies. We conducted a large statewide observational study among TN adult decedents (2013-2016) to evaluate the association of sociodemographic factors and prescribing patterns with opioid overdose deaths. METHODS: Among drug overdose decedents identified using death certificate data (n = 5483), we used logistic regression to estimate adjusted odds ratios and 95% confidence intervals for characteristics associated with prescription opioid (PO) (excluding fentanyl), fentanyl, and heroin alone overdoses. Among decedents linked to TN's Prescription Drug Monitoring Database using deterministic algorithms, we obtained prescription history in the year before death (n = 3971), which was evaluated by type of overdose using descriptive statistics. RESULTS: Younger, non-White decedents had lower odds of PO overdose, while females and benzodiazepines as a contributing cause were associated with increased odds of PO overdose. Younger age, Non-Hispanic Black race/ethnicity, greater than high school education, and cocaine/other stimulants as a contributing cause were associated with increased odds of fentanyl or heroin overdoses. Over 55% of PO, 39.2% of fentanyl, and 20.7% of heroin overdoses had an active opioid prescription at death. For PO, fentanyl, and heroin decedents, respectively, 46.0%, 30.5%, and 26.2% had an active prescription for benzodiazepines at death. CONCLUSIONS: Prescription opioid overdose deaths were associated with different sociodemographic profiles and prescribing history compared to fentanyl and heroin overdose deaths in TN. Data can guide prevention strategies to reduce opioid overdose mortality.

Public Health Policy Strategies to Address the Opioid Epidemic.

Public health policy responses to the opioid epidemic require addressing both opioid supply and opioid demand. The growth in prescriptions of opioid analgesics, for example, is associated with escalating opioid overdose fatalities.1 Enhanced access to opioid agonist treatment, conversely, is required to curb demands driven by opioid use disorders. Oregon's multidimensional approaches toward opioid misuse and abuse achieved 20% reductions in opioid prescribing and a 30% reduction in the opioid overdose fatality rate.

Using Controlled Substance Receipt Patterns to Predict Prescription Overdose Death.

BACKGROUND: This study evaluates complete state data from controlled substance prescribing trends in the prescription monitoring program (PMP) database and their association with the risk of prescription drug overdose death. SUMMARY: Maine PMP records of individuals who died of prescription overdose deaths between 2006 and 2010 were selected (n = 690). For each subject, an age, gender, and residence matched cohort of PMP users in a 50: 1 ratio was identified (n = 34,500). Key Messages: Prescription opioids contributed to 480 of 690 prescription deaths, many co-ingestions were noted, and OR for overdose death increased with milligram of morphine equivalent (MME)/day >100. The majority who were prescribed MME >100 per day received a prescription within 90 days of overdose matching the toxicology cause of death. CONCLUSIONS: Medication profiles available through state PMP can identify dosing of prescriptions associated with drug overdose death.

Overdose Epidemic, Prescription Monitoring Programs, and Public Health: A Review of State Laws.

Prescription monitoring programs (PMPs), state-level databases that collect patient-specific prescription information at the time medications are dispensed, have been suggested as tools to address the overdose epidemic. We reviewed all laws in the United States (n = 25) that articulated the purposes PMPs are intended to serve. Attributes related to reducing abuse, misuse, and diversion of prescription medications appeared most commonly. Only 5 purpose statements mentioned the promotion of public health as goals of the PMP, and only 3 listed improving health care. None listed overdose prevention as a goal of the PMP.

Development of an algorithm to identify serious opioid toxicity in children.

BACKGROUND: The use of opioids is increasing in children; therefore, opioid toxicity could be a public health problem in this vulnerable population. However, we are not aware of a published algorithm to identify cases of opioid toxicity in children using administrative databases. We sought to develop an algorithm to identify them. After review of literature and de-identified computer profiles, a broad set of ICD-9 CM codes consistent with serious opioid toxicity was selected. Based on these codes, we identified 195 potential cases of opioid toxicity in children enrolled in Tennessee Medicaid. Medical records were independently reviewed by two physicians; episodes considered equivocal were reviewed by an adjudication committee. Cases were adjudicated as Group 1 (definite/probable), Group 2 (possible), or Group 3 (excluded). RESULTS: Of the 195 potential cases, 168 (86.2%) had complete records for review and 85 were confirmed cases. The overall positive predictive value (PPV) for all codes was 50.6%. The PPV for codes indicating: unintentional opioid overdose (25/31) was 80.7%; intentional opioid overdose (15/30) was 50.0%, adverse events (33/58) was 56.9%, the presence of signs or symptoms compatible with opioid toxicity (12/47) was 25.5%, and no cases were confirmed in records from the two deaths. Of the confirmed cases, 65.8% were related to therapeutic opioid use. CONCLUSION: For studies utilizing administrative claims to quantify incidence of opioid toxicity in children, our findings suggest that use of a broad set of screening codes coupled with medical record review is important to increase the completeness of case ascertainment.

Responding to opioid overdose in Rhode Island: where the medical community has gone and where we need to go.

The number of opioid overdose events in Rhode Island has increased dramatically/catastrophically in the last decade; Rhode Island now has one of the highest per capita overdose death rates in the country. Healthcare professionals have an important role to play in the reduction of unintentional opioid overdose events. This article explores the medical community's response to the local opioid overdose epidemic and proposes strategies to create a more collaborative and comprehensive response. We emphasize the need for improvements in preventing, identifying and treating opioid addiction, providing overdose education and ensuring access to the rescue medicine naloxone.

Individual patient assessment of methadone-induced QT prolongation with digital holter recording.

A 27-year-old male who had been on methadone therapy for 6 months was investigated with a 12-lead digital holter because of a prolonged QT on a standard 12-lead electrocardiogram (ECG). The patient had 24-hour holter recording on and off methadone therapy and multiple digitized 12-lead ECG data were captured for on-screen measurement of the QT interval. For each 24-hour period QT-HR pairs were plotted on the QT nomogram showing QT prolongation on methadone but not when it was ceased. This provides a highly accurate method for evaluating drug-induced QT prolongation.

Selecting an appropriate biomonitoring strategy to evaluate dermal exposure to opioid narcotic analgesics in pharmaceutical production workers.

OBJECTIVES: In a follow-up study of previous research, in which exposure pathways for opioid narcotic analgesics were identified in pharmaceutical workers involved in drug synthesis, the current research focused on the selection of an appropriate biomonitoring strategy. METHODS: Six opioid narcotic production workers were intensively monitored during a (1 week) fentanyl production campaign. A systematic sampling scheme was followed that provided information about hand contamination and biomarker levels at multiple time points. RESULTS: Linear mixed-effects models, incorporating half-shift and end-of-shift hand contamination levels, showed a positive and significant correlation with fentanyl urinary excretion occurring at many of the 4 h time lags investigated (4-28 h). Optimum model characteristics, including both minimal between- and within-worker variability, were obtained at lag times of 24 h and 20 h, respectively, advocating a pre-shift urine sampling strategy on the following day. In addition, for these lag times the portion of the variability explained by the model was maximal. Furthermore, using a distributed lag model, it was demonstrated that urinary fentanyl levels were positively correlated with hand contamination levels measured at the preceding four 8 h time lags (8-32 h), although statistical significance was only shown for a lag time of 24 h. CONCLUSION: Fentanyl levels in pre-shift urine samples reflect dermal exposure to the compound during the previous day. Thus, in the specific working environment investigated, a biological monitoring protocol evaluating pre-shift urinary fentanyl levels could provide an adequate risk estimate in individual workers.

Toxicological evaluation of mu-agonists. Part II: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo-alpha-noracetylmethadol HCl (NorLAAM).

This study evaluated levo-alpha-noracetylmethadol (NorLAAM), the first N-demethylated metabolite of levo-alpha-acetylmethadol (LAAM), a long-acting morphine-like (mu) agonist, approved in 1993 to treat opiate dependence. After acute and 7-day pilot studies to define dose levels appropriate for use in longer term evaluations, Sprague-Dawley rats (20 of each sex per group) were gavaged with doses of 4.4-25.9 mg kg(-1) day(-1) for 30 days followed by a 14-day recovery period. Treatment-related effects included dose-dependent CNS depression paralleled by changes in food consumption, body weight gain and fecal output, as well as reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound primarily in its time course. Cage-biting and gnawing behavior were observed only with NorLAAM. Mortality was dose-dependent, with deaths occurring predominantly during the first week. At day 30, all male-treated groups exhibited statistically significant, dose-dependent decreases in body weight gain and increases in serum cholesterol that returned to the control range following recovery. Increases in brain/body weight and testes/body weight ratios and decreases in kidney/brain, liver/brain, spleen/brain and heart/brain ratios, as well as decreases in kidney, liver, spleen and heart absolute weights, achieved statistical significance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral deposition in mid- and high-dose groups of both sexes and of corticomedullary mineral deposition in females. Hepatic centrilobular hypertrophy was evident in male and female mid- and high-dose groups. Histopathological changes abated following the recovery period. In summary, acute and repeated administration of NorLAAM produced a pharmacodynamic profile commensurate with its role as the primary N-demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent compound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its activity as a mu-agonist, which stimulates hepatic microsomal enzymes in rodents.