oxymorphone and Drug-Overdose

Topics: Adult; Analgesics, Opioid; Diagnosis, Differential; Drug Overdose; Emergency Medical Services; Hearing Loss, Sensorineural; Humans; Insufflation; Internet; Male; Massachusetts; Oxymorphone; Receptors, Opioid, mu; Treatment Outcome

Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches.. A preparation of pooled human liver microsomes was used to study oxycodone metabolism in the presence or absence of diazepam or diclazepam. In mice, diazepam or diclazepam was concomitantly administered with oxycodone to mimic acute intoxication. Diclazepam was introduced on Day 10 in mice continuously infused with oxycodone for 15 days to mimic chronic intoxication. In silico modelling was used to study the molecular interactions of the three drugs with CYP3A4 and 2D6.. In mice, in acute conditions, both diazepam and diclazepam inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6.. Acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage.. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Topics: Analgesics, Opioid; Animals; Benzodiazepines; Cytochrome P-450 CYP3A; Diazepam; Drug Overdose; Humans; Mice; Models, Animal; Oxycodone; Oxymorphone

Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription opioid black market. This study examined variables that may influence the street price of diverted oxycodone and oxymorphone.. A cross-sectional study was conducted utilizing data from the previously validated, crowdsourcing website StreetRx. Street price reports of selected oxycodone and oxymorphone products, between August 22, 2014 and June 30, 2016, were considered for analysis. Geometric means and 95% confidence intervals were calculated comparing prices per milligram of drug in US dollars. Univariate and multivariable regressions were used to examine the influence of dosage strength, drug formulation, and bulk purchasing on street price.. A total of 5611 oxycodone and 1420 oxymorphone reports were analyzed. Across various dosages and formulations, geometric mean prices per milligram ranged between $0.12 and $1.07 for oxycodone and $0.73 and $2.90 for oxymorphone. For a 2-fold increase in dosage strength, there is a 24.0% (95% CI: -28.1%, -19.6%, P < 0.001) and a 22.5% (95% CI: -24.2%, -20.8%, P < 0.001) decrease on average in price per milligram for oxycodone and oxymorphone, respectively. Lower potency, high dosage strength, crush-resistant opioids, and those purchased in bulk were significantly cheaper.. Street prices for diverted oxycodone and oxymorphone are influenced by multiple factors including potency, dosage, formulation, and bulk purchasing. Buyers who purchase large quantities of low potency, large dosage, crush-resistant formulation prescription opioids can expect to achieve the lowest price.

Topics: Commerce; Cross-Sectional Studies; Drug Overdose; Humans; Illicit Drugs; Narcotics; Opioid-Related Disorders; Oxycodone; Oxymorphone; Prescription Drug Diversion; Prospective Studies; United States

It is reasonable to expect the presence of multiple drugs to present a complicated picture of toxicity. We report a fatal case involving a young man who purchased illicit drugs and knowingly consumed them. After consuming these drugs and going to sleep in his friend's car, he was found unresponsive the next morning with no signs of physical violence. Drugs found in the peripheral blood at autopsy were oxymorphone, methylone and ethanol at concentrations of 0.106, 0.50 and 130 mg/dL, respectively. The levels of oxymorphone and methylone in peripheral blood were comparable to those observed in other reported fatalities. Cocaine and benzoylecgonine were detected in the urine but not in the blood. Measureable concentrations were also observed for oxymorphone and methylone in urine, liver, kidney and bile. The physical findings at autopsy included pulmonary edema. This is the only reported fatal case involving this combination of drugs encountered in our laboratory.

Topics: Adult; Drug Overdose; Ethanol; Fatal Outcome; Forensic Toxicology; Humans; Male; Methamphetamine; Oxymorphone; Pulmonary Edema

A sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the quantitation of oxymorphone (OM) in human whole blood and liver. Sample preparation was done by solid-phase extraction, using deuterated OM as the internal standard. Separation was achieved using a Waters Aquity UPLC HSS T3 column. Analysis utilized positive electrospray ionization and multiple reaction monitoring. As part of the validation, studies were conducted to determine potential interference, selectivity, ion suppression/enhancement and carryover. Calibration model, limit of detection (LOD), lower limit of quantitation (LLOQ), precision and accuracy were also established. The linear range of the method was 2-500 ng/mL in blood and 5-500 ng/g in the liver. The LOD and LLOQ were 2 ng/mL for blood and 5 ng/g for the liver. Blood and/or liver specimens from 30 cases were analyzed. OM concentrations ranged from 23 to 554 ng/mL ( , n = 26) in blood and 48 to 1740 ng/g ( , n = 30) in the liver.

Topics: Adult; Autopsy; Calibration; Cause of Death; Chromatography, High Pressure Liquid; Drug Overdose; Female; Humans; Limit of Detection; Linear Models; Liver; Male; Middle Aged; Oxymorphone; Reproducibility of Results; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Tissue Distribution; Young Adult

Topics: Analgesics, Opioid; Cross Reactions; Diagnosis; Drug Overdose; Enzyme-Linked Immunosorbent Assay; Humans; Opioid-Related Disorders; Oxycodone; Oxymorphone; Substance Abuse Detection

Two cases are reported involving the abuse of extended-release oxymorphone hydrochloride tablets (Opana® ER) in combination with alprazolam (Xanax®). Two juvenile females were discovered unresponsive and hypoxic by a male acquaintance. The trio had reportedly crushed and snorted Opana ER tablets and consumed Xanax for recreational purposes. Emergency personnel were able to stabilize one female. The second female was pronounced dead at the scene. Blood and urine samples from the surviving female were collected at the trauma center between 48 and 96 h post incident. Toxicology results showed the presence of oxymorphone, doxylamine, dextromethorphan, alprazolam, α-hydroxyalprazolam, oxazepam, and temazepam in her urine. No drugs were detected in her blood. Toxicology on the deceased female revealed the presence of 0.13 mg/L oxymorphone and 0.04 mg/L alprazolam in her blood. Gastric contents contained 0.25 and 0.93 mg/L of oxymorphone and alprazolam, respectively. Oxymorphone, alprazolam, and α-hydroxyalprazolam were present in her urine. Quantitative results were achieved by gas chromatography-mass spectrometry monitoring selected ions for the oxime-oxymorphone-trimethylsilyl derivative, alprazolam, and the α-hydroxyalprazolam tert-butyldimethylsilyl derivative. The established linearity ranges for the opiate and benzodiazepine methods were 0.050-3.000 and 0.025-1.000 mg/L, respectively. The cause of death was reported as multiple drug toxicity, and the manner of death was accidental.

Topics: Administration, Intranasal; Analgesics, Opioid; Drug Overdose; Fatal Outcome; Female; Gas Chromatography-Mass Spectrometry; Humans; Narcotics; Oxymorphone; Substance-Related Disorders; Tablets

Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine-overdose victims. The number of D3 binding sites was increased one-to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine-overdose victims, as compared to age-matched and drug-free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine-overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine-overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.

Topics: Autoradiography; Brain; Cause of Death; Cocaine; Dopamine Agonists; Drug Overdose; Gene Expression Regulation; Humans; Iodine Radioisotopes; Limbic System; Nucleus Accumbens; Oxymorphone; Peptidylprolyl Isomerase; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid, kappa; Tetrahydronaphthalenes; Transcription, Genetic; Tritium