Pharmacologic and Clinical Considerations of Nalmefene, a Long Duration Opioid Antagonist, in Opioid Overdose

Opioid use disorder is a well-established and growing problem in the United States. It is responsible for both psychosocial and physical damage to the affected individuals with a significant mortality rate. Given both the medical and non-medical consequences of this epidemic, it is important to understand the current treatments and approaches to opioid use disorder and acute opioid overdose. Naloxone is a competitive mu-opioid receptor antagonist that is used for the reversal of opioid intoxication. When given intravenously, naloxone has an onset of action of approximately 2 min with a duration of action of 60–90 min. Related to its empirical dosing and short duration of action, frequent monitoring of the patient is required so that the effects of opioid toxicity, namely respiratory depression, do not return to wreak havoc. Nalmefene is a pure opioid antagonist structurally similar to naltrexone that can serve as an alternative antidote for reversing respiratory depression associated with acute opioid overdose. Nalmefene is also known as 6-methylene naltrexone. Its main features of interest are its prolonged duration of action that surpasses most opioids and its ability to serve as an antidote for acute opioid overdose. This can be pivotal in reducing healthcare costs, increasing patient satisfaction, and redistributing the time that healthcare staff spend monitoring opioid overdose patients given naloxone.

PATHOMORPHOGENESIS OF LIVER STEATOSIS IN PATIENTS WITH OPIOID DEPENDENCE

Background. One of the significant factors in the progression of fibrotic changes in the liver is hepatocyte steatosis, that persists in drug addicted patients even after the elimination of the hepatitis C virus and cessation of drug use. Analysis of the pathomorphogenesis of hepatic steatosis in opioid dependence (OZ) will make it possible to assess the factors that affect ultrastructural changes in hepatocytes and the processes of lipid granule (LH) degradation. Objective. Assessment of ultrastructural changes in LH in the liver tissue of patients with OZ. Material and methods. Histological preparations of liver tissue from 20 patients with OZ aged 21 to 40 years (18 men and 2 women) with different duration of OZ and opioid tolerance. Results. There was established the following dependence of ultrastructural changes in the liver in patients with different duration of OZ and opioid tolerance. The most pronounced changes were noted in the group of patients with prolonged (more than 6 years) opioid intoxication and high tolerance to opioids in the liver tissue, in whom, along with severe steatosis, there were more significant violations of the mechanisms of LH degradation, destruction of cristae in mitochondria, a decrease in the number of lipophagosomes and PH with signs of superficial degradation than in the group of patients with OZ duration up to 6 years, as well as with moderate and high opioid tolerance. Conclusions. Ultrastructural changes in hepatocytes in the form of progression of steatosis in the centrilobular and periportal zones, a decrease in the activity of LH degradation, gross morphological changes in mitochondria, a decrease in the activity of surface LH degradation depend on the activity and duration of opioid dependence and are more pronounced with long-term (more than 6 years) highly progressive opioid dependence.

Differential Expression of NPAS4 in the Dorsolateral Prefrontal Cortex Following Acute Opioid Intoxication

Background and AimsThe physical, emotional, and social impacts of opioid abuse are well known; although preclinical models reveal the neurobiological pathways altered through opioid abuse, comprehensive assessments of gene expression in human brain samples are lacking. The goals of the present study were to compare gene expression in the prefrontal cortex between brain samples of individuals who died of acute opioid intoxication and group-matched controls, and to test if differential gene expression was enriched in gene sets related to opioid use.DesignCross-sectional study using human brains donated to the Lieber Institute for Brain Development. Study groups included 72 brain samples from individuals who died of acute opioid intoxication, 53 group-matched psychiatric control samples, and 28 group-matched normal control samples.SettingMaryland, USA.ParticipantsPostmortem tissue samples of the dorsolateral prefrontal cortex from 153 deceased individuals (Mage = 35.42, SD = 9.43 years; 62% male; 77% White).MeasurementsWhole transcriptome RNA sequencing was used to generate exon counts, and differential expression was tested using limma-voom. Analyses controlled for relevant sociodemographic characteristics, technical covariates, and cryptic relatedness and batch effects using quality surrogate variable analysis. Gene set enrichment analyses (GSEA) also were conducted.FindingsSixteen genes were differentially expressed (i.e., FDR-corrected p < .10) in opioid samples compared to control samples. The top differentially expressed gene, NPAS4 (FDR adjusted p = .005), was downregulated in opioid samples and has previously been implicated in cocaine use. Enrichment analyses did not provide evidence for enrichment in pathways obviously related to opioid use.ConclusionsNPAS4 is differentially expressed in the prefrontal cortex of subjects that died of an opioid overdose, providing evidence for another gene with functional relevance to opioid use and overdose.

Epigenome-Wide Study of Brain DNA Methylation Among Opioid Users and Controls

Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis (EWAS) of DNA methylation in brains of individuals who died from opioid intoxication and controls. Tissue samples were extracted from the dorsolateral prefrontal cortex of 160 deceased individuals (Mage = 35.15, SD = 9.42 years; 62% male; 78% White). The samples included 73 individuals who died of opioid intoxication, 59 group-matched psychiatric controls, and 28 group-matched normal controls. EWAS was implemented using the Illumina Infinium MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control and ancestry principal components, cellular composition, and surrogate variables. Epigenetic age was calculated using the Horvath and Levine clocks, and gene ontology (GO) analyses were performed. No CpG sites were epigenome-wide significant after multiple testing correction, but 13 sites reached nominal significance (p < 1.0 x 10-5). There was a significant association between opioid use and Levine phenotypic age (b = 2.24, se = 1.11, p = .045). Opioid users were approximately two years phenotypically older compared to controls. GO analyses revealed enriched pathways related to cell function and neuron differentiation, but no terms survived multiple testing correction. Results inform our understanding of the neurobiology of opioid use, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse.

Aspiration in lethal drug abuse—a consequence of opioid intoxication

Aims The primary objective of this study was to investigate whether the fatalities of opioid abuse are not only related to respiratory depression but also as a result of other side effects such as emesis, delayed gastric emptying, a reduction of the cough reflex, and impaired consciousness leading to the aspiration of gastric contents, a finding regularly observed in drug-related deaths. Design A retrospective exploratory study analyzing heroin/morphine/methadone-related deaths submitted to court-ordered autopsy. Setting Center for Forensic Medicine, Medical University of Vienna, Austria (2010–2015). Participants Two hundred thirty-four autopsy cases were included in the study: morphine (n = 200), heroin (n = 11), and methadone (n = 23) intoxication. Findings Analyses revealed that 41.88% of all deceased showed aspiration of gastric contents with equal gender distribution (p = 0.59). Aspiration was more frequent in younger deceased (χ2 = 8.7936; p = 0.012) and in deceased with higher body mass index (BMI) (χ2 = 6.2441; p = 0.044). Blood opioid concentration was lower in deceased with signs of aspiration than in non-aspirators (p = 0.013). Toxicological evaluation revealed a high degree of concomitant substance abuse (91%)—benzodiazepines (61.6%) and/or alcohol (21.8%). Conclusions There are lower opioid concentrations in deceased with signs of aspiration, a fact which strongly points to aspiration as alternative cause of death in opioid-related fatalities. Furthermore, this study highlights the common abuse of slow-release oral morphine in Vienna and discusses alternative medications in substitution programs (buprenorphine/naloxone or tamper-resistant slow-release oral morphine preparations), as they might reduce intravenous abuse and opioid-related deaths.

Incidence and correlates of opioid-related psychiatric emergency care: A retrospective, multiyear cohort study

Background: In 2018, nearly 4,000 Canadian lives were claimed by the opioid epidemic. To date, only a few studies have reviewed shifts in emergency department (ED) utilization for opioid-related psychiatric presentations. Aims: To describe the characteristics of patients seeking ED care for opioid-related psychiatric presentations and to identify demographic and clinical characteristics that were associated with psychiatric inpatient admission for such presentations.Methods: Retrospective cohort study with multivariate logistic regression.Findings: Over a 4-year period, 555 opioid-related presentations were recorded (50 percent female, mean age 40.0 years). Time trend analysis showed a nonsignificant increase in the number of visits by fiscal year. The most common reason for ED presentation relevant to opioids was opioid withdrawal (49 percent). Nearly 20 percent of all visits required psychiatric admission; predictors of psychiatric admission were arrival by ambulance (adjusted odds ratio (AOR) = 2.03), older age (AOR = 1.05), longer length of ED stay (AOR = 1.10), and more severe triage score (AOR = 0.4). Sex and referring service were not associated with disposition in the ED. Admissions were more likely for opioid intoxication and withdrawal.Conclusion: EDs are serving increasing numbers of patients in psychiatric crisis related to opioid-use. A decision support tool could be developed and validated in the future to provide reliable, clinically relevant information to providers and case managers relevant to opioid-related ED presentations.