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A sensitive and reliable LC-MS/MS method was developed and validated for the quantification of oxycodone and metabolites in human plasma. The method has a runtime of 6 min and a sensitivity of 0.1 µg/L for all analytes. Sample preparation consisted of protein precipitation. Separation was performed on a Kinetix biphenyl column (2.1 × 100 mm, 1.7 µm), using ammonium formate 5 mm in 0.1% aqueous formic acid and methanol LC-MS grade 100% in gradient elution at a flow rate of 0.4 ml/min. Detection was performed in multiple reaction monitoring mode using positive electrospray ionization. The method was linear over the calibration range of 0.1-25.0 µg/L for oxycodone, noroxycodone and noroxymorphone and 0.1-5.0 µg/L for oxymorphone. The method demonstrated good performance in terms of intra- and interday accuracy (86.5-110.3%) and precision (CV 1.7-9.3%). The criteria for the matrix effect were met (CV < 15%) except for noroxymorphone, for which an additional method was applied to compensate for the matrix effect. Whole blood samples were stable for 4 h at room temperature. Plasma samples were stable for 24 h at room temperature and 3 months at -20°C. Furthermore, the method was successfully applied in a pharmacokinetic drug interaction study of oxycodone and enzalutamide in patients with prostate cancer.
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Oxicodona , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Oxicodona/sangre , Oxicodona/farmacocinética , Oxicodona/química , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Modelos Lineales , Interacciones Farmacológicas , Masculino , Morfinanos/sangre , Morfinanos/farmacocinética , Morfinanos/química , Límite de Detección , Oximorfona/sangre , Oximorfona/química , Oximorfona/farmacocinética , Sensibilidad y Especificidad , Estabilidad de Medicamentos , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.
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Oxicodona , Oximorfona , Humanos , Oxicodona/farmacocinética , Oximorfona/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Cetoconazol/farmacología , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A , Inhibidores de Disociación de Guanina Nucleótido , Glucuronosiltransferasa/genéticaRESUMEN
The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the risks presented by opioid exposure, as well as the individual risk profiles of specific opioid drugs and the potential relationships among the opioids. In this study, 92 opioids were identified from the list of all Food and Drug Administration (FDA)-approved drugs, annotated by RxNorm and were classified into 13 opioid groups: buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol. A total of 14,970,399 AE reports were retrieved and downloaded from the FDA Adverse Events Reporting System (FAERS) from 2004, Quarter 1 to 2020, Quarter 3. After data processing, Empirical Bayes Geometric Mean (EBGM) was then applied which identified 3317 pairs of potential risk signals within the 13 opioid groups. Based on these potential safety signals, a comparative analysis was pursued to provide a global overview of opioid-related AEs for all 13 groups of FDA-approved prescription opioids. The top 10 most reported AEs for each opioid class were then presented. Both network analysis and hierarchical clustering analysis were conducted to further explore the relationship between opioids. Results from the network analysis revealed a close association among fentanyl, oxycodone, hydrocodone, and hydromorphone, which shared more than 22 AEs. In addition, much less commonly reported AEs were shared among dihydrocodeine, meperidine, oxymorphone, and tapentadol. On the contrary, the hierarchical clustering analysis further categorized the 13 opioid classes into two groups by comparing the full profiles of presence/absence of AEs. The results of network analysis and hierarchical clustering analysis were not only consistent and cross-validated each other but also provided a better and deeper understanding of the associations and relationships between the 13 opioid groups with respect to their adverse effect profiles.
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Analgésicos Opioides , Oxicodona , Analgésicos Opioides/efectos adversos , Teorema de Bayes , Minería de Datos , Fentanilo , Hidrocodona , Hidromorfona , Meperidina , Oximorfona , Tapentadol , Estados Unidos/epidemiologíaRESUMEN
Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.
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Analgésicos Opioides , Oximorfona , Analgésicos Opioides/farmacología , Oximorfona/farmacología , Preparaciones Farmacéuticas , Dopamina/metabolismo , Naloxona/farmacología , Receptores Opioides mu/metabolismoRESUMEN
Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.
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Antígenos de Grupos Sanguíneos , Neoplasias , Humanos , Detección Precoz del Cáncer , Histona Desacetilasa 6 , Bexaroteno , Oximorfona , Inmunoterapia , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVE: Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone. METHODS: A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. RESULTS: Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC0-8 h and Cmax of oxycodone with, respectively, 44.7% (p < 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC0-8 h and Cmax of the active metabolite oxymorphone were 74.2% (p < 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC0-8 h and Cmax of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide. CONCLUSION: Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.
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Oxicodona , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Oximorfona/metabolismo , Cromatografía Liquida/métodos , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Espectrometría de Masas en Tándem/métodos , Analgésicos Opioides , DolorRESUMEN
BACKGROUND AND OBJECTIVE: While the current landscape of opioid use disorder (OUD) is complicated by the increase in use of non-prescription opioids, prescription opioids continue to be frequently used in non-medical ways. In response to this abuse, pharmaceutical companies have developed abuse deterrent formulations (ADFs) for extended-release (ER) opioids. To test the effectiveness of Xtampza ER ADF (oxycodone myristate) at reducing tampering, its rate of tampering in a treatment-center population was compared to immediate release (IR) single entity (SE) oxycodone, other ER oxycodone opioids, and ER oxymorphone. METHODS: Data were collected between the third quarter of 2018 and the third quarter of 2021 from individuals entering nationally distributed opioid treatment programs. To determine odds of tampering with Xtampza ER compared to each comparator, a logistic model was fit with a random intercept allowing for multiple drugs in each subject. Within-subject correlation was assumed to have a compound symmetric relationship. RESULTS: Overlap among the categories of drug tampering was high. Logistic regression analyses found that oxycodone myristate had lower odds of tampering when compared to both IR SE oxycodone (OR = 0.23 [95% CI 0.11, 0.50], p = 0.0002) and ER oxymorphone (OR = 0.30 [95% CI 0.14, 0.67], p = 0.0038). Oxycodone myristate was not significantly different from other ER oxycodone opioids (OR = 0.5 [95% CI 0.24, 1.03], p = 0.0612). These findings did not change when the estimates were adjusted for age and sex. CONCLUSIONS: Drugs employing ADF technology may reduce the likelihood of tampering when compared to non-ADF formulations in a treatment-center population, which represents an opportunity for intervention in OUD among those still requiring pain management.
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Formulaciones Disuasorias del Abuso , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Oxicodona/uso terapéutico , Estudios Transversales , Oximorfona/efectos adversos , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/prevención & control , Trastornos Relacionados con Opioides/tratamiento farmacológico , Preparaciones de Acción RetardadaRESUMEN
BACKGROUND: Urine drug testing (UDT) monitors prescription compliance and/or drug abuse. However, interpretation of UDT results obtained by liquid chromatography-tandem mass spectrometry (LC-MS-MS) can be complicated by the presence of drug impurities that are detected by highly sensitive methods. Hydrocodone is a drug impurity that can be found as high as 1% in oxycodone pills. OBJECTIVES: We evaluated the frequency and concentration of hydrocodone and its metabolite, hydromorphone, in patients taking oxycodone to check if the ratio of hydrocodone or hydromorphone to oxycodone could distinguish between oxycodone only use from those consuming additional opiates. DESIGN & METHODS: We correlated LC-MS/MS results with medication records of 319 patients with positive oxycodone results over 7 months (4/2021-11/2021). RESULTS: Fifteen of 319 patients with positive oxycodone results were taking oxycodone only. For these 15 patients, the mean ratio of hydrocodone to oxycodone was 0.57% (range 0.05%-3.35%), and the mean ratio of hydromorphone to oxycodone was 0.81% (range 0.18-3.51%). CONCLUSIONS: Hydrocodone and/or hydromorphone are detectable in patients taking only oxycodone and can likely be identified as an impurity if their calculated ratio to oxycodone is <1 %. Further validation of the ratios in a larger sample size is recommended.
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Hidrocodona , Trastornos Relacionados con Opioides , Humanos , Hidrocodona/análisis , Hidromorfona/análisis , Oxicodona , Analgésicos Opioides , Cromatografía Liquida/métodos , Oximorfona , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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. LINKED ARTICLES: 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.
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Sobredosis de Droga , Oxicodona , Humanos , Animales , Ratones , Oximorfona , Citocromo P-450 CYP3A , Benzodiazepinas/toxicidad , Diazepam/farmacología , Analgésicos Opioides/toxicidad , Modelos AnimalesRESUMEN
Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. SIGNIFICANCE STATEMENT: Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.
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Encéfalo , Proteínas de Homeodominio , Oxicodona , Oximorfona , Analgésicos Opioides/farmacología , Animales , Encéfalo/efectos de los fármacos , Femenino , Proteínas de Homeodominio/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Oxicodona/farmacología , Oximorfona/farmacología , RecompensaRESUMEN
To avoid a positive urine drug test, donors might try to subvert the test, either by adulterating the specimen with a product designed to interfere with testing or by substituting the specimen for a synthetic urine. A market search conducted in December of 2020 identified 3 adulterants and 32 synthetic urines, and a selection was procured based on specific criteria. Samples prepared with the 3 adulterants and 10 synthetic urines were submitted for testing at five forensic drug testing laboratories to perform immunoassay screening, chromatographic confirmation analysis and specimen validity testing (SVT). One adulterant determined to contain iodate reduced THC-COOH concentrations by 65% and the concentrations of 6-acetylmorphine, morphine, oxycodone, oxymorphone, hydrocodone and hydromorphone by 6-27%. Another adulterant determined to contain nitrite reduced THC-COOH concentrations by 22%, while the third did not affect drug screening or confirmatory testing. Both active adulterants could be identified through positive oxidant screens as well as through signal suppression in cloned enzyme donor immunoassay (CEDIA). The synthetic urines could not be identified either through traditional SVT or by the AdultaCheck10 dipstick. The Synthetic UrineCheck dipstick produced a difference in response between the authentic urine specimen and the synthetic urine samples, but the difference was small and difficult to observe. While most synthetic urines now contain uric acid, magnesium and caffeine, the results indicated that a biomarker panel including endogenous and exogenous markers of authentic urine performed well and clearly demonstrated the absence of biomarkers in the synthetic urines. The SVT assay also offers potential targets for future screening assays.
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Dronabinol , Detección de Abuso de Sustancias , Hidrocodona , Inmunoensayo , Oximorfona , Detección de Abuso de Sustancias/métodosRESUMEN
A rapid, simple extraction method followed by qualitative screening using liquid chromatography-tandem mass spectrometry (LC-MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council's Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid-liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid-buffer mix collected in a Quantisal™ device, followed by LC-MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory.
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3,4-Metilenodioxianfetamina , Buprenorfina , Carisoprodol , Cocaína , Meprobamato , Metanfetamina , N-Metil-3,4-metilenodioxianfetamina , Tramadol , 2-Propanol , Alprazolam , Anfetaminas , Clonazepam , Codeína , Dronabinol , Fentanilo , Hexanos , Hidrocodona , Hidromorfona , Lorazepam , Metadona , Derivados de la Morfina , Nordazepam , Oxazepam , Oxicodona , Oximorfona , Preparaciones Farmacéuticas/análisis , Fenciclidina , Espectrometría de Masas en Tándem , Temazepam , ZolpidemRESUMEN
Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 h before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and sham-operated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pre-treatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.
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Analgesia , Oxicodona , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Encéfalo/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Estradiol/metabolismo , Ciclo Estral/metabolismo , Femenino , Masculino , Oxicodona/farmacología , Oximorfona/metabolismo , Dolor/metabolismo , Progesterona/metabolismo , Propranolol/metabolismo , Ratas , Ratas WistarRESUMEN
ABSTRACT: The United States is enduring a preventable opioid crisis, particularly involving a population being treated in a hospital setting, a subset of whom may escalate to illicit opioids. This project analyzed trends in distribution of opioids by hospitals in the United States. Opioids monitored included buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, powdered opium, remifentanil, and tapentadol. The Automation of Reports and Consolidated Orders System (ARCOS) reports on substances controlled by the Drug Enforcement Administration. National data from ARCOS reports 5 and 7 from 2000 to 2019 were used for an observational study on hospital opioid distribution. Morphine milligram equivalents (MMEs) were calculated using oral conversion factors. The MME per person per state was calculated to compare data from the peak year, 2012, with data from 2019. Opioid use peaked in 2012, with a -46.6% decline from 2012 to 2019. Half (25) of the states have seen a decrease of -50% or greater. Of the opioid compounds observed, buprenorphine has seen increased (+122.5%) hospital use from 2012 to 2019. All other opioids have been experiencing a decline (≥50%), particularly hydromorphone (-49.9%), oxymorphone (-57.7%), methadone (-58.7%), morphine (-66.9%), codeine (-67.5%), and meperidine (-77.6%). There was a 6-fold difference in population-corrected use of opioids in 2019 between the lowest (6.8 MME/person in New Jersey) and highest (Alaska = 39.6) states. This study demonstrates the considerable progress made thus far by hospitals in curbing the U.S. opioid crisis.
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Analgésicos Opioides , Buprenorfina , Analgésicos Opioides/uso terapéutico , Buprenorfina/uso terapéutico , Codeína , Hospitales , Humanos , Hidromorfona/uso terapéutico , Meperidina , Metadona , Morfina , Oximorfona , Estados Unidos/epidemiologíaRESUMEN
The purpose of this research was to develop and validate an analytical method for the detection and quantification of noroxymorphone-3ß-D-glucuronide (NOMG), oxymorphone-3ß-D-glucuronide (NOMG), noroxymorphone (NOM), oxymorphone (OM), 6α-oxycodol (αOCL), 6ß-oxycodol (ßOCL), noroxycodone (NOC) and oxycodone (OC) in urine by liquid chromatography tandem mass spectrometry to be used in a human study. The method was validated according to the Academy Standards Board Standard Practices for Method Development in Forensic Toxicology. The method was then applied to a single-dose pilot study of a subject. Urine samples were collected from the subject after ingesting 10-mg OC as an immediate-release tablet. Additionally, urine specimens (n = 15) that had previously been confirmed positive for OC were analyzed using the validated method. The calibration range for NOMG and OMG was 0.05-10 µg/mL; for all other analytes, it was 0.015-10 µg/mL. Validation parameters such as bias, precision, carryover and dilution integrity, all met the validation criteria. After the method was validated, urine samples from the first subject in the controlled dose study were analyzed. It was observed that OC, NOC and OMG contained the highest concentrations and were present in either the 0.5 or 1 h void. NOC and OMG were detected until the 48 h collection, while OC was detectable till the 24 h collection. Time to reach maximum concentration (Tmax) in the urine was achieved within 1.5 h for OC and within 3 h for NOC and OMG. Maximum concentration (Cmax) in the urine for OC, NOC and OMG was 3.15, 2.0 and 1.56 µg/mg, respectively. OC concentrations in authentic urines ranged from 0.015 to 12 µg/mL. Ranges for NOMG and OMG were 0.054-9.7 µg/mL and 0.14-67 µg/mL, respectively. A comprehensive method for the quantification of NOMG, OMG, NOM, OM, αOCL, ßOCL, NOC and OC in urine was optimized and met the validation criteria. The concentrations of NOMG and OMG presented in this study provide the details needed in the forensic community to better comprehend OC pharmacokinetics.
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Oxicodona , Espectrometría de Masas en Tándem , Cromatografía Liquida , Humanos , Oximorfona , Proyectos PilotoRESUMEN
There is a need to develop a novel analgesic for pain associated with interstitial cystitis/painful bladder syndrome (IC/PBS). The use of the conventional µ-opioid receptor agonists to manage IC/PBS pain is controversial due to adverse CNS effects. These effects are attenuated in benzylideneoxymorphone (BOM), a low-efficacy µ-opioid receptor agonist/δ-opioid receptor antagonist that attenuates thermal pain and is devoid of reinforcing effects. We hypothesize that BOM will inhibit bladder pain by attenuating responses of urinary bladder distension (UBD)-sensitive afferent fibers. Therefore, the effect of BOM was tested on responses of UBD-sensitive afferent fibers in L6 dorsal root from inflamed and non-inflamed bladder of rats. Immunohistochemical (IHC) examination reveals that following the induction of inflammation there were significant high expressions of µ, δ, and µ-δ heteromer receptors in DRG. BOM dose-dependently (1-10 mg/kg, i.v) attenuated mechanotransduction properties of these afferent fibers from inflamed but not from non-inflamed rats. In behavioral model of bladder pain, BOM significantly attenuated visceromotor responses (VMRs) to UBD only in inflamed group of rats when injected either systemically (10 mg/kg, i.v.) or locally into the bladder (0.1 ml of 10 mg/ml). Furthermore, oxymorphone (OXM), a high-efficacy µ-opioid receptor agonist, attenuated responses of mechanosensitive bladder afferent fibers and VMRs to UBD. Naloxone (10 mg/kg, i.v.) significantly reversed the inhibitory effects of BOM and OXM on responses of bladder afferent fibers and VMRs suggesting µ-opioid receptor-related analgesic effects of these compounds. The results reveal that a low-efficacy, bifunctional opioid-based compound can produce analgesia by attenuating mechanotransduction functions of afferent fibers innervating the urinary bladder.
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Analgésicos/farmacología , Compuestos de Bencilideno/farmacología , Cistitis Intersticial/fisiopatología , Mecanotransducción Celular/efectos de los fármacos , Oximorfona/farmacología , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Raíces Nerviosas Espinales/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Vías Aferentes , Animales , Cistitis Intersticial/metabolismo , Modelos Animales de Enfermedad , Vértebras Lumbares , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Oximorfona/análogos & derivados , Ratas , Raíces Nerviosas Espinales/metabolismoRESUMEN
AIMS: Intravenous (IV) misuse of the µ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aims of this pilot study were to directly compare IV oxymorphone to IV oxycodone, morphine, and hydromorphone on a subjective measure of drug liking and to assess relative potency. METHODS: Participants (n = 6) with opioid use disorder, physical dependence, and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70 kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32), and placebo. Data were collected before and for 6 h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking, and relative potency estimates. RESULTS: All active test drugs produced prototypical, dose-related µ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p < 0.05). Across abuse-related subjective outcomes, oxymorphone was 2.3-2.8-fold more potent than hydromorphone and 12.5-14-fold more potent than oxycodone (p < 0.05). CONCLUSIONS: Despite the relatively small sample size, this pilot study detected robust oxymorphone effects. Oxymorphone was far more potent than the comparator opioids, particularly on abuse potential outcomes. Overall, these findings may help explain surveillance reports that demonstrate, after adjusting for prescription availability, oxymorphone is injected at the highest frequency, relative to other prescription opioids.
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Trastornos Relacionados con Opioides , Oximorfona , Analgésicos Opioides/efectos adversos , Humanos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Oxicodona , Oximorfona/efectos adversos , Proyectos PilotoRESUMEN
INTRODUCTION: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. AIMS: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. METHODS: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). RESULTS: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84-124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83-122%. CONCLUSION: A LC-MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS.
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Oximorfona , Tramadol , Anciano , Cromatografía Liquida , Fentanilo/análogos & derivados , Humanos , Morfinanos , Oxicodona , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Tramadol/análogos & derivadosRESUMEN
BACKGROUND: Cancer patients often require feeding or venting gastrostomy-tubes (G-tubes) for enteral nutrition or symptom palliation. The administration of most extended-release (ER) opioids via the G-tube or orally followed by clamping of the venting G-tube is contraindicated. Oxymorphone immediate release (IR) may be useful because of its longer half-life compared to other IR opioids. We examined the use of oxymorphone IR administered every 8 hours in patients with G-tubes. METHODS: This was a retrospective chart review of 40 consecutive cancer patients with G-tubes who underwent opioid rotation (OR) to oxymorphone. Demographics, symptoms, morphine equivalent daily dose (MEDD), and oxymorphone dose were collected. Successful OR was defined as a 2-point or 30% reduction in pain score and continued use of oxymorphone at follow-up in outpatient setting, or discharge in inpatient setting. Opioid rotation ration (ORR) between MEDD and oxymorphone in patients with successful OR was calculated as MEDD before the OR divided by total oxymorphone dose/day at follow-up or discharge. RESULTS: The median age was 56 years, 57.5% were white, 68% male, 47.5% (n=19) had head and neck cancer, 90% had advanced disease, 67.5% (n=27) were inpatient, and 15% (n=6) had venting G-tubes. 25/40 (62.5%) patients had successful OR to oxymorphone. The median ORR from MEDD to oxymorphone was 3.5 (IQR, 3.1-4). There were no independent predictors for successful OR, and ORR did not significantly differ among various groups. CONCLUSIONS: Oxymorphone IR can be used successfully in cancer patients with G-tubes using an ORR of 3.5 to calculate dose from MEDD.
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Neoplasias , Oximorfona , Analgésicos Opioides/uso terapéutico , Femenino , Gastrostomía , Humanos , Masculino , Persona de Mediana Edad , Oximorfona/uso terapéutico , Dolor , Estudios RetrospectivosRESUMEN
RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at µ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other µ opioid receptor agonists. OBJECTIVES: The current study compared the acute behavioral effects of BOM with the effects of other µ opioid receptor agonists. METHODS: Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration. RESULTS: BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration. CONCLUSIONS: Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by µ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.