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Scientific Reports Mar 2020Morphine and structurally-derived compounds are µ opioid receptor (µOR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by...
Morphine and structurally-derived compounds are µ opioid receptor (µOR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by serious side effects, including dependence and abuse potential. The N-substituent in morphinans plays an important role in opioid activities in vitro and in vivo. This study presents the synthesis and pharmacological evaluation of new N-phenethyl substituted 14-O-methylmorphinan-6-ones. Whereas substitution of the N-methyl substituent in morphine (1) and oxymorphone (2) by an N-phenethyl group enhances binding affinity, selectivity and agonist potency at the µOR of 1a and 2a, the N-phenethyl substitution in 14-methoxy-N-methylmorphinan-6-ones (3 and 4) converts selective µOR ligands into dual µ/δOR agonists (3a and 4a). Contrary to N-methylmorphinans 1-4, the N-phenethyl substituted morphinans 1a-4a produce effective and potent antinociception without motor impairment in mice. Using docking and molecular dynamics simulations with the µOR, we establish that N-methylmorphinans 1-4 and their N-phenethyl counterparts 1a-4a share several essential receptor-ligand interactions, but also interaction pattern differences related to specific structural features, thus providing a structural basis for their pharmacological profiles. The emerged structure-activity relationships in this class of morphinans provide important information for tuning in vitro and in vivo opioid activities towards discovery of effective and safer analgesics.
Topics: Analgesics, Opioid; Animals; CHO Cells; Cell Line; Cricetulus; Humans; Ligands; Male; Mice; Morphinans; Morphine; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship
PubMed: 32221355
DOI: 10.1038/s41598-020-62530-w -
American Journal of Therapeutics 2016According to the Food and Drug Administration (FDA) reports, approximately 8 in 10 prescriptions filled in the United States are for generic medications, with an... (Review)
Review
According to the Food and Drug Administration (FDA) reports, approximately 8 in 10 prescriptions filled in the United States are for generic medications, with an expectation that this number will increase over the next few years. The impetus for this emphasis on generics is the cost disparity between them and brand-name products. The use of FDA-approved generic drugs saved 158 billion dollars in 2010 alone. In the current health care climate, there is continually increasing pressure for prescribers to write for generic alternative medications, occasionally at the expense of best clinical practices. This creates a conflict wherein both physicians and patients may find brand-name medications clinically superior but nevertheless choose generic ones. The issue of generic versus brand medications is a key component of the discussion of health payers, physicians and their patients. This review evaluates some of the important medications in the armamentarium of pain physicians that are frequently used in the management of chronic pain, and that are currently at the forefront of this issue, including Opana (oxymorphone; Endo Pharmaceuticals, Inc., Malvern, PA), Gralise (gabapentin; Depomed, Newark, CA), and Horizant (gabapentin enacarbil; XenoPort, Santa Clara, CA) that are each available in generic forms as well. We also discuss the use of Lyrica (pregabalin; Pfizer, New York, NY), which is currently unavailable as generic medication, and Cymbalta (duloxetine; Eli Lilly, Indianapolis, IN), which has been recently FDA approved to be available in a generic form. It is clear that the use of generic medications results in large financial savings for the cost of prescriptions on a national scale. However, cost-analysis is only part of the equation when treating chronic pain patients and undervalues the relationships of enhanced compliance due to single-daily dosing and stable and reliable pharmacokinetics associated with extended-duration preparations using either retentive technologies or delayed absorption strategies. Medications given to chronic pain patients should be individualized to best serve analgesic needs and assure patient safety primarily, based on high levels of scientific and economic evidence. Decisions regarding utilization should not be made based solely on limited or faulty assessments of cost-benefit analyses.
Topics: Amines; Carbamates; Chronic Pain; Cyclohexanecarboxylic Acids; Drugs, Generic; Duloxetine Hydrochloride; Gabapentin; Humans; Oxymorphone; Pregabalin; gamma-Aminobutyric Acid
PubMed: 24914505
DOI: 10.1097/MJT.0000000000000098 -
Journal of Chromatography. B,... May 2021The objective of this study was to develop and validate a highly sensitive method for the detection of oxycodone, noroxycodone, 6β-oxycodol, 6α-oxycodol, oxymorphone,...
The objective of this study was to develop and validate a highly sensitive method for the detection of oxycodone, noroxycodone, 6β-oxycodol, 6α-oxycodol, oxymorphone, and noroxymorphone in blood by liquid chromatography tandem mass spectrometry. The analytes were extracted from blood (0.5 mL) using Bond Elut Certify Solid Phase Extraction columns, evaporated to dryness and reconstituted before analysis was performed on an Acquity UPLC® I-class coupled to a Waters Xevo TQD. Academy Standards Board Standard Practices for Method Development in Forensic Toxicology were used for the validation of this method. The limit of quantitation for all analytes was established at 0.5 ng/mL. Calibration range for noroxymorphone, oxymorphone, 6α-oxycodol and 6β-oxycodol was 0.5-25 ng/mL and 0.5-100 ng/mL for noroxycodone and oxycodone. Precision (2.90-17.3%) and bias studies resulted in a ±15% deviation. There were no interferences observed from internal standard, matrix, or common drugs of abuse. Stability of all analytes at two concentrations at 24, 48, and 72 h in the autosampler did not exceed ±20% difference from the initial T. Dilution integrity at a ten-fold dilution was acceptable as analyte concentrations ranged between (±18%) of the target concentration. Once validated, the method was used in a pilot dosing study of one male subject after taking a 10 mg immediate release tablet of oxycodone. Blood samples were collected at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 9, and 24 h after ingestion. Oxycodone and noroxycodone both reached T at 1.5 h and had C values of 25.9 and 12.8 ng/mL, respectively. Oxycodone, 6α-oxycodol, and 6β-oxycodol were detectable up to 9 h, while noroxymorphone and noroxycodone were still detected at 24 h.
Topics: Chromatography, High Pressure Liquid; Humans; Limit of Detection; Linear Models; Male; Morphinans; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 33744597
DOI: 10.1016/j.jchromb.2021.122625 -
MedRxiv : the Preprint Server For... May 2024Chronic pain affects one fifth of American adults, contributing significant public health burden. Chronic pain mechanisms can be further understood through investigating...
BACKGROUND
Chronic pain affects one fifth of American adults, contributing significant public health burden. Chronic pain mechanisms can be further understood through investigating brain gene expression.
METHODS
We tested differentially expressed genes (DEGs) in chronic pain, migraine, lifetime fentanyl and oxymorphone use, and with chronic pain genetic risk in four brain regions (dACC, DLPFC, MeA, BLA) and imputed cell type expression data from 304 postmortem donors. We compared findings across traits and with independent transcriptomics resources, and performed gene-set enrichment.
RESULTS
We identified two chronic pain DEGs: B4GALT and VEGFB in bulk dACC. We found over 2000 (primarily BLA microglia) chronic pain cell type DEGs. Findings were enriched for mouse microglia pain genes, and for hypoxia and immune response. Cross-trait DEG overlap was minimal.
CONCLUSIONS
Chronic pain-associated gene expression is heterogeneous across cell type, largely distinct from that in pain-related traits, and shows BLA microglia are a key cell type.
PubMed: 38826319
DOI: 10.1101/2024.05.20.24307630 -
Journal of Pain & Palliative Care... Dec 2016We conducted a systematic review to evaluate worldwide human English published literature from 2009 to 2014 on prevalence of opioid misuse/abuse in retrospective... (Review)
Review
We conducted a systematic review to evaluate worldwide human English published literature from 2009 to 2014 on prevalence of opioid misuse/abuse in retrospective databases where International Classification of Diseases (ICD) codes were used. Inclusion criteria for the studies were use of a retrospective database, measured abuse, dependence, and/or poisoning using ICD codes, stated prevalence or it could be derived, and documented time frame. A meta-analysis was not performed. A qualitative narrative synthesis was used, and 16 studies were included for data abstraction. ICD code use varies; 10 studies used ICD codes that encompassed all three terms: abuse, dependence, or poisoning. Eight studies limited determination of misuse/abuse to an opioid user population. Abuse prevalence among opioid users in commercial databases using all three terms of ICD codes varied depending on the opioid; 21 per 1000 persons (reformulated extended-release oxymorphone; 2011-2012) to 113 per 1000 persons (immediate-release opioids; 2010-2011). Abuse prevalence in general populations using all three ICD code terms ranged from 1.15 per 1000 persons (commercial; 6 months 2010) to 8.7 per 1000 persons (Medicaid; 2002-2003). Prevalence increased over time. When similar ICD codes are used, the highest prevalence is in US government-insured populations. Limiting population to continuous opioid users increases prevalence. Prevalence varies depending on ICD codes used, population, time frame, and years studied. Researchers using ICD codes to determine opioid abuse prevalence need to be aware of cautions and limitations.
Topics: Analgesics, Opioid; Databases, Factual; Humans; International Classification of Diseases; Opioid-Related Disorders; Prescription Drug Misuse; Prevalence
PubMed: 27802072
DOI: 10.1080/15360288.2016.1231739 -
International Journal of Environmental... May 2020There have been dynamic changes in prescription opioid use in the US but the state level policy factors contributing to these are incompletely understood. We examined...
There have been dynamic changes in prescription opioid use in the US but the state level policy factors contributing to these are incompletely understood. We examined the association between the legalization of recreational marijuana and prescription opioid distribution in Colorado. Utah and Maryland, two states that had not legalized recreational marijuana, were selected for comparison. Prescription data reported to the Drug Enforcement Administration for nine opioids used for pain (e.g., fentanyl, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone) and two primarily for opioid use disorder (OUD, methadone and buprenorphine) from 2007 to 2017 were evaluated. Analysis of the interval pre (2007-2012) versus post (2013-2017) marijuana legalization revealed statistically significant decreases for Colorado ( < 0.05) and Maryland ( < 0.01), but not Utah, for pain medications. There was a larger reduction from 2012 to 2017 in Colorado (-31.5%) than the other states (-14.2% to -23.5%). Colorado had a significantly greater decrease in codeine and oxymorphone than the comparison states. The most prevalent opioids by morphine equivalents were oxycodone and methadone. Due to rapid and pronounced changes in prescription opioid distribution over the past decade, additional study with more states is needed to determine whether cannabis policy was associated with reductions in opioids used for chronic pain.
Topics: Analgesics, Opioid; Cannabis; Colorado; Humans; Legislation, Drug; Maryland; Oxycodone; Practice Patterns, Physicians'; United States
PubMed: 32392702
DOI: 10.3390/ijerph17093251 -
Journal of Analytical Toxicology Feb 2021Oxycodone (OC) is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of OC concentrations in postmortem cases is...
Oxycodone (OC) is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of OC concentrations in postmortem cases is complicated due to tolerance and overlapping concentrations for fatal and non-fatal levels. In this study, our aim was to develop and validate a method for OC and its three metabolites: noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM) in postmortem femoral blood. Our goal was to define reference concentrations for intoxications and non-intoxications and investigate metabolic ratios in different causes of death. A rapid LC-MS-MS method using protein-precipitated postmortem blood was developed. Lower limit of quantitation was 0.005 μg/g blood for all analytes; upper limit of quantitation was 1.0 μg/g for OC and NOC and 0.25 μg/g for OM and NOM. The method displayed high precision (3.3-7.7%) and low bias (-0.3 to 12%). In total, 192 cases were analyzed and concentrations ranged from 0.005 to 13 μg/g for OC, 0.005 to 2.0 μg/g for NOC, 0.005 to 0.24 μg/g for OM, and 0.005 to 0.075 μg/g for NOM. We found a significant difference in OC concentration between the cases where OC contributed and those where it did not. In spite of that, we do not recommend the use of a specific blood concentration to distinguish fatal intoxications. Instead, the percentiles from our data set suggest that concentrations >0.2 μg/g are likely to have contributed to toxicity, but that concentrations as high as 0.3 might be tolerated without toxic effects. In addition, we also found that a low NOC/OC ratio could point toward an acute fatal intoxication. In conclusion, the OC concentration alone may not be sufficient to diagnose a fatal intoxication.
Topics: Chromatography, Liquid; Forensic Toxicology; Humans; Opiate Overdose; Oxycodone; Substance Abuse Detection; Tandem Mass Spectrometry
PubMed: 32435814
DOI: 10.1093/jat/bkaa051 -
Drug and Alcohol Dependence Sep 2018For a number of fiscal and practical reasons, data on heroin use have been of poor quality, which has hampered the ability to halt the growing epidemic. Internet search...
BACKGROUND
For a number of fiscal and practical reasons, data on heroin use have been of poor quality, which has hampered the ability to halt the growing epidemic. Internet search data, such as those made available by Google Trends, have been used as a low-cost, real-time data source for monitoring and predicting a variety of public health outcomes. We aimed to determine whether data on opioid-related internet searches might predict future heroin-related admissions to emergency departments (ED).
METHODS
Across nine metropolitan statistical areas (MSAs) in the United States, we obtained data on Google searches for prescription and non-prescription opioids, as well as Substance Abuse and Mental Health Services Administration (SAMHSA) data on heroin-related ED visits from 2004 to 2011. A linear mixed model assessed the relationship between opioid-related Internet searches and following year heroin-related visits, controlling for MSA GINI index and total number of ED visits.
RESULTS
The best-fitting model explained 72% of the variance in heroin-related ED visits. The final model included the search keywords "Avinza," "Brown Sugar," "China White," "Codeine," "Kadian," "Methadone," and "Oxymorphone." We found regional differences in where and how people searched for opioid-related information.
CONCLUSIONS
Internet search-based modeling should be explored as a new source of insights for predicting heroin-related admissions. In geographic regions where no current heroin-related data exist, Internet search modeling might be a particularly valuable and inexpensive tool for estimating changing heroin use trends. We discuss the immediate implications for using this approach to assist in managing opioid-related morbidity and mortality in the United States.
Topics: Adult; Analgesics, Opioid; Emergency Service, Hospital; Female; Forecasting; Heroin Dependence; Humans; Internet; Linear Models; Male; Patient Admission; Pilot Projects; Predictive Value of Tests; Public Health; United States; United States Substance Abuse and Mental Health Services Administration
PubMed: 30036853
DOI: 10.1016/j.drugalcdep.2018.05.009 -
Addiction Biology Mar 2019Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor...
Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P < 0.03) and analgesia (1.5-fold AUC ; P < 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6-fold; P < 0.001) and decreased analgesia (0.8-fold; P < 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P > 0.1) and analgesia (1.1-fold; P > 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P < 0.003), but not hepatic (P > 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P > 0.9 for AUC across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability.
Topics: Administration, Oral; Analgesics, Opioid; Analysis of Variance; Animals; Blood-Brain Barrier; Brain; Cytochrome P450 Family 2; Male; Nociception; Oxycodone; Pain; Pain Measurement; Rats, Wistar
PubMed: 29266563
DOI: 10.1111/adb.12590 -
Acta Anaesthesiologica Scandinavica May 2020Parenteral opioids are used for pain relief in labour but there are little data for oxycodone in this context. The aim of this study was to evaluate the efficacy, foetal...
BACKGROUND
Parenteral opioids are used for pain relief in labour but there are little data for oxycodone in this context. The aim of this study was to evaluate the efficacy, foetal exposure and safety of subcutaneous oxycodone in the latent phase of labour.
METHODS
This pragmatic trial included 76 parturients, who received subcutaneous oxycodone for pain relief in the latent phase of labour according to the hospital protocol: an initial dose 0.1 mg/kg, and a second dose, 0.05 mg/kg, could be administered four hours later. Pain intensity and pain relief were assessed using a numerical rating scale of 0-10. After delivery, blood samples from the maternal and umbilical veins were collected, and plasma concentrations of oxycodone and its main metabolites were quantified using UPLC-MS/MS. The Apgar scores and maternal and neonatal adverse effects were recorded.
RESULTS
The foetal exposure at birth was low, the median oxycodone and oxymorphone umbilical vein plasma concentrations were 1.2 ng/mL (range 0.21-7.8) and 0.14 ng/mL (0-0.26), respectively. Pain scores decreased substantially, from a median pain score of 7/10 before oxycodone to median scores of 5/10 at 30 minutes after administration, 5/10 at 60 minutes and 6/10 at 120 minutes. The median Apgar score was 9 (range 2-10) at 1 minute and 9 (6-10) at 5 minutes. Maternal adverse effects were mild, and there were no oxycodone-related neonatal adverse effects.
CONCLUSION
Subcutaneous oxycodone provided effective analgesia during the latent phase of labour. Newborn exposure at birth was low, and oxycodone was well-tolerated.
Topics: Adult; Analgesia, Obstetrical; Analgesics, Opioid; Female; Finland; Humans; Labor Pain; Labor, Obstetric; Oxycodone; Pain Management; Pregnancy; Young Adult
PubMed: 31950485
DOI: 10.1111/aas.13550