Identification of Morphine and Heroin-Treatment in Mice Using Metabonomics

Although heroin and morphine are structural analogues and morphine is a metabolite of heroin, it is not known how the effect of each substance on metabolites in vivo differs. Heroin and morphine were administered to C57BL/6J mice in increasing doses from 2 to 25 and 3 to 9 mg kg−1 (twice a day, i.p.), respectively, for 20 days. The animals underwent withdrawal for 5 days and were readministered the drugs after 10 days. Serum and urine analytes were profiled using gas chromatography-mass spectrometry (GC-MS), and metabolic patterns were evaluated based on metabonomics data. Metabonomics data showed that heroin administration changed metabolic pattern, and heroin withdrawal did not quickly restore it to baseline levels. A relapse of heroin exposure changed metabolic pattern again. In contrast, although the administration of morphine changed metabolic pattern, whether from morphine withdrawal or relapse, metabolic pattern was similar to control levels. The analysis of metabolites showed that both heroin and morphine interfered with lipid metabolism, the tricarboxylic acid (TCA) cycle and amino acid metabolism. In addition, both heroin and morphine increased the levels of 3-hydroxybutyric acid and citric acid but decreased the serum levels of 2-ketoglutaric acid and tryptophan. Moreover, heroin and morphine reduced the levels of aconitic acid, cysteine, glycine, and oxalic acid in urine. The results show 3-Hydroxybutyric acid, tryptophan, citric acid and 2-ketoglutaric acid can be used as potential markers of opiate abuse in serum, while oxalic acid, aconitic acid, cysteine, and glycine can be used as potential markers in urine.

Add-On Selective Estrogen Receptor Modulators for Methadone Maintenance Treatment

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism.

Association of miR-155, miR-187 and Inflammatory Cytokines Il-10 and TNF-α in Chronic Opiate Abusers

The current study determined levels of inflammatory cytokines TNF-α, IL-6, IL-10 and immune-regulatory miR-155 and miR-187 expressions in chronic opiate abuse. Adults (n = 48), meeting the 5th Edition of the DSM criteria regarding opioid use disorder, and healthy controls (n = 46) were included in the study. Serum samples were analysed for inflammatory cytokines IL-10, IL-6, TNF-α using ELISA and PBMCs processed for miRNA expression using SybrGreen chemistry. Cases showed significantly raised IL-10 and TNF-α and reduced IL-6. Using RNU6 for normalization, dose-dependent corresponding upregulation of miR-155-5p and downregulation of miR-187-5p were evident at opiate dose > 1500 gm/day, with a corresponding increase of TNF-α and IL-10. MiR-155 showed a significant negative correlation with IL-6 and TNF-α; miR-187 showed a significant positive association with TNF-α at > 1000 g/day consumption. Therefore, increasing consumption of opium probably enhances inflammation leading to immunomodulation and aberrant expression of has-miR-155-5p and has-miR-187-5p in opiate abusers.

Candida infective endocarditis: A retrospective study of patient characteristics and risk factors for death in 703 U.S. cases, 2015-2019

Background Candida endocarditis is a rare, sometimes fatal complication of candidemia. Past investigations of this condition are limited by small sample sizes. We used the Vizient clinical database to report on characteristics of patients with Candida endocarditis and to examine risk factors for in-hospital mortality. Methods This was a multicenter, retrospective cohort study of 703 inpatients admitted to 179 United States hospitals between October 2015 and April 2019. We reviewed demographic, diagnostic, medication administration, and procedural data from each patient’s initial encounter. Univariate and multivariate logistic regression analyses were used to identify predictors of in-hospital mortality. Results Of 703 patients, 114 (16.2%) died during the index encounter. One hundred and fifty-eight (22.5%) underwent an intervention on a cardiac valve. On multivariate analysis, acute and subacute liver failure was the strongest predictor of death (OR 9.2, 95% CI 4.8 –17.7). Female sex (OR 1.9, 95% CI 1.2 – 3.0), transfer from an outside medical facility (OR 1.8, 95% CI 1.1 – 2.8), aortic valve pathology (OR 2.7, 95% CI 1.5 – 4.9), hemodialysis (OR 2.1, 95% CI 1.1 – 4.0), cerebrovascular disease (OR 2.2, 95% CI 1.2 – 3.8), neutropenia (OR 2.5, 95% CI 1.3 – 4.8), and alcohol abuse (OR 2.9, 95% CI 1.3 – 6.7) were also associated with death on adjusted analysis, whereas opiate abuse was associated with a lower odds of death (OR 0.5, 95% CI 0.2 – 0.9). Conclusions We found that the inpatient mortality rate was 16.2% among patients with Candida endocarditis. Acute and subacute liver failure was associated with a high risk of death while opiate abuse was associated with a lower risk of death.

The Crushing Effects Of Opiate Abuse: Two Cases Illustrating The Morphologic Features Of Acute And Chronic Intravenous Administration Of Crushed Oral Opiates

Introduction/Objective Drug overdose related deaths in the US have shown a four-fold increase over the past two decades, increasing from 6.1 to 21.7 per 100,000, the increasing majority of which involve synthetic opioid use. With this continuing increase, it is important for pathologists to become aware of unusual gross and microscopic changes related to unconventional modes of drug abuse. A less recognized unconventional method for opiate abusers to ingest these substances exemplified by our two cases is by crushing oral tablets and inhaling or injecting the drug intravenously, subcutaneously or intramuscularly. Methods The two cases being presented show morphological features of acute and chronic opiate abuse by autopsy study. Case 1 was a 38-year old female, who underwent spinal fusion surgery 1 month prior, and was found unresponsive at home. Case 2 was a 37-year-old female with a history of Antiphospholipid Antibody Syndrome (APA) and upper limb DVTs who was found unresponsive one day after elective utero-vaginal prolapse surgery. Results At autopsy, Case 1 showed extensive embolization of polarizable foreign body material (possible “pill filler”) and fibrin in small and medium sized vessels without inflammatory reaction in the lungs bilaterally. The foreign material was also present in the small vessels of the heart associated with multifocal acute inflammation, hemorrhage, foreign body giant cell reaction and multiple myocardial infarcts (elevated troponin levels clinically). Blood and vitreous fluid were positive for oxycodone. At autopsy, Case 2 showed an extensive angiocentric miliary pattern of granulomatous reaction to polarizable foreign material, consistent with pill filler in the lungs bilaterally. This foreign material was also present within the lumens and walls of pulmonary vessels and in the skin of the legs. Chronic changes of hypertrophic cardiomyopathy, hepatic cirrhosis and congestive splenomegaly were evident. The blood oxycodone levels were ten times the normal limit. Conclusion These cases illustrate the importance of recognizing the clinical and morphological features of unorthodox acute and chronic opiate abuse. Lack of familiarity with their differing features can lead to a delay in diagnosis and institution of appropriate timely management and treatment.

1178. Risk factors for death among patients with Candida endocarditis: An observational study in US academic medical centers

Background Candida endocarditis is a rare, sometimes fatal complication candidemia. Our understanding of this condition is limited to findings from case series and small observational studies. Using the Vizient clinical database, a repository for clinical and administrative data from 117 academic medical centers and more than 300 affiliated hospitals, we assembled the largest cohort of Candida endocarditis patients to date, reporting patient characteristics and risk factors for death. Methods Using ICD-10 code B37.6 (Candidal Endocarditis) we identified 703 inpatients at 179 United States hospitals from October 2015 through April 2019. We examined demographic, diagnostic, and procedural data from each patient’s initial encounter. With univariate and multivariate logistic regression analyses we identified predictors of in-hospital mortality. Results Of 703 patients, 402 (57.2%) were male, 421 (59.9%) used tobacco, 213 (30.3%) had documented opiate abuse, 128 (18.2%) had other illicit drug abuse documented, and 190 (27.0%) had documented hepatitis C infection. Among the 703 patients, 114 (16.2%) died during the index encounter. On multivariate analysis, liver failure was the strongest predictor of death (OR 8.4, 95% CI 4.4 – 15.9), and female sex (OR 1.8, 95% CI 1.1 – 2.9), transfer from an outside facility (OR 1.7, 95% CI 1.1 – 2.7), underlying aortic valve pathology (OR 2.8, 95% CI 1.5 – 4.9), hemodialysis (OR 2.0, 95% CI 1.0 – 3.8), cerebrovascular disease (OR 2.2, 95% CI 1.2 – 3.8), neutropenia (OR 2.5, 95% CI 1.3 – 4.7) and alcohol abuse (OR 2.9, 95% CI 1.3 – 6.7) were also associated with higher odds of in-hospital death. In the same analysis, opiate abuse was associated with a lower odds of in-hospital death (OR 0.4, 95% CI 0.2 – 0.8). Table 1. Characteristics of 703 patients with Candida endocarditis Table 2. Factors associated with in-hospital death in multivariate regression analysis Conclusion We found that for patients Candida endocarditis inpatient mortality was 16.2% and liver failure was associated with a high risk of death while opiate abuse was protective. Further investigation is necessary to better understand these associations. Disclosures Michael Z. David, MD PhD, GSK (Consultant)

A Case Report: Co-presenting COVID-19 Infection and Acute Drug Intoxication

Background: Coronavirus disease 2019 (COVID-19) has spread throughout the world since late 2019. Symptoms appear after a two-week incubation period and commonly include fever, cough, myalgia or fatigue, and shortness of breath. Case Report: A 32-year-old male with a history of opiate abuse presented to the emergency department with altered mental status. The patient was lethargic and hypoxic with improvement from naloxone. Official chest radiograph was read as normal; however, the treating clinicians noted bilateral interstitial opacities, raising concern for underlying infectious etiology. Opiates and cocaine were positive on drug screen, and an arterial blood gas on room air showed hypoxemia with respiratory acidosis. The patient was intubated during the treatment course due to persistent hypoxemia and for airway protection after resuscitation. The COVID-19 test was positive on admission, and later computed tomography showed ground-glass opacities. The patient was extubated and discharged after one week on the ventilator. Conclusion: When screening patients at and during evaluation, physicans should consider a broad differential as patients with atypical presentations may be overlooked as candidates for COVID-19 testing. As screening and evaluation protocols evolve, we emphasize maintaining a high index of suspicion for COVID-19 in patients with atypical symptoms or presenting with other chief complaints in order to avoid spreading the disease.

Metabolomics in Central Sensitivity Syndromes

Central sensitization syndromes are a collection of frequently painful disorders that contribute to decreased quality of life and increased risk of opiate abuse. Although these disorders cause significant morbidity, they frequently lack reliable diagnostic tests. As such, technologies that can identify key moieties in central sensitization disorders may contribute to the identification of novel therapeutic targets and more precise treatment options. The analysis of small molecules in biological samples through metabolomics has improved greatly and may be the technology needed to identify key moieties in difficult to diagnose diseases. In this review, we discuss the current state of metabolomics as it relates to central sensitization disorders. From initial literature review until Feb 2020, PubMed, Embase, and Scopus were searched for applicable studies. We included cohort studies, case series, and interventional studies of both adults and children affected by central sensitivity syndromes. The majority of metabolomic studies addressing a CSS found significantly altered metabolites that allowed for differentiation of CSS patients from healthy controls. Therefore, the published literature overwhelmingly supports the use of metabolomics in CSS. Further research into these altered metabolites and their respective metabolic pathways may provide more reliable and effective therapeutics for these syndromes.

Validity of the screener and opioid assessment for patients with pain-revised (SOAPP-R) in patients with cancer

Objective: To determine the utility of the screener and opioid assessment for patients with pain-revised (SOAPP-R) for patients with cancer-related pain. Design: The authors performed a retrospective analysis of cancer patients screened with the SOAPP-R. Opiate abuse was determined using a combination of urine drug screens and analysis of patients’ electronic medical records.Setting/Patients: Patients who were seen at a palliative care clinic presenting with pain or needing an opioid prescription at an academic medical center with any type of cancer were screened using the SOAPP-R (N = 69).Outcome measures: Aberrant opioid-related behavior was determined using a combination of provider notes and urine drug screens.Results: A positive SOAPP-R score (≥18) was observed in 27 participants (39.1 percent). The sensitivity and specificity of the SOAPP-R in the study population was 0.75 and 0.80, respectively.Conclusions: The SOAPP-R, in its current form, may have value in screening patients with cancer for substance abuse. Incorporation of the screening tool in palliative and oncology settings may help reduce opioid abuse in cancer patients.