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Journal of Opioid Management 2022To determine equianalgesic potency ratios for opioids with an -evidence-based approach without the use of pre-existing potency tables. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine equianalgesic potency ratios for opioids with an -evidence-based approach without the use of pre-existing potency tables.
DESIGN
Frequentist network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing opioids in patient-controlled analgesia (PCA).
SETTING
A systematic review.
DATA SOURCES
A systematic search of MEDLINE, EMBASE, the Cochrane Library (CENTRAL), and Web of Science identified relevant RCTs from start of recording to 2019.
ELIGIBILITY CRITERIA
RCTs comparing opioids via intravenous PCA in acute pain, with comparable resulting pain scores and identical treatment with coanalgesics at study level. The quality of studies was assessed using the Cochrane risk of bias tool with six items.
RESULTS
52 RCTs were identified with data for 16 opioids. Primary endpoint was the inverted ratio of means of the total consumption administered via PCA, which resembles the analgesic potency. The calculated analgesic potencies were sufentanil 423 [95 percent CI 334.99; 532.96], fentanyl 58 [48.22; 68.60], buprenorphine 37 [26.66; 50.81], remifentanil 13 [9.37; 19.13], alfentanil 7 [4.02; 11.01], hydromorphone 6 [4.96; 8.43], oxymorphone 6 [4.46; 8.84], butorphanol 4.5 [3.05; 6.73], diamorphine 2.2 [1.16; 4.10], morphine 1, oxycodone 0.9 [0.65; 1.34], piritramide 0.9 [0.55; 1.56], nalbuphine 0.7 [0.54; 0.95], pethidine 0.12 [0.10; 0.15], meptazinol 0.08 [0.03; 0.20], and tramadol 0.08 [0.07; 0.10].
CONCLUSIONS
The results in part contradict the values from the literature, which have been criticized for their imprecision. From clinical experience however, our findings seem very plausible. Short-acting opioids are less potent compared to longer acting drugs, eg, morphine, probably due to shorter intervals for -readministration.
Topics: Humans; Analgesia, Patient-Controlled; Analgesics, Opioid; Network Meta-Analysis; Tramadol; Morphine
PubMed: 36523208
DOI: 10.5055/jom.2022.0751 -
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 Analytical Toxicology Feb 2022The purpose of this research was to develop and validate an analytical method for the detection and quantification of noroxymorphone-3β-D-glucuronide (NOMG),...
The purpose of this research was to develop and validate an analytical method for the detection and quantification of noroxymorphone-3β-D-glucuronide (NOMG), oxymorphone-3β-D-glucuronide (NOMG), noroxymorphone (NOM), oxymorphone (OM), 6α-oxycodol (αOCL), 6β-oxycodol (βOCL), 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, βOCL, 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.
Topics: Chromatography, Liquid; Humans; Oxycodone; Oxymorphone; Pilot Projects; Tandem Mass Spectrometry
PubMed: 33270113
DOI: 10.1093/jat/bkaa186 -
The Medical Letter on Drugs and... Dec 2022
Topics: Humans; Analgesics, Opioid; Codeine; Administration, Cutaneous; Oxycodone; Morphine
PubMed: 36541939
DOI: No ID Found -
Pharmacoepidemiology and Drug Safety Jan 2019Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription...
PURPOSE
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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
PubMed: 29766592
DOI: 10.1002/pds.4558 -
Drug Metabolism and Disposition: the... Feb 2020Oxycodone is used as a potent analgesic medication. Oxycodone is extensively metabolized. To fully describe its metabolism, the oxygenation of oxycodone to oxycodone...
Oxycodone is used as a potent analgesic medication. Oxycodone is extensively metabolized. To fully describe its metabolism, the oxygenation of oxycodone to oxycodone N-oxide was investigated in hepatic preparations. The hypothesis tested was that oxycodone -oxygenation was enzymatic and the amount of N-oxide detected was a consequence of both oxygenation and retro-reduction. Methods for testing the hypothesis included both in vitro and in vivo studies. Results indicated that oxycodone was -oxygenated by the flavin-containing monooxygenase. Oxycodone N-oxide is chemically quite stable but in the presence of hepatic preparations and NADPH was retro-reduced to its parent compound oxycodone. Subsequently, oxycodone was metabolized to other metabolites including noroxycodone, noroxymorphone, and oxymorphone via cytochrome P-450. Retro-reduction of oxycodone N-oxide to oxycodone was facilitated by quinone reductase, aldehyde oxidase, and hemoglobin but not to a great extent by cytochrome P-450 or the flavin-containing monooxygenase. To confirm the in vitro observations, oxycodone was administered to rats and humans. In good agreement with in vitro results, substantial oxycodone N-oxide was observed in urine after oxycodone administration to rats and humans. Administration of oxycodone N-oxide to rats showed substantial amount of recovered oxycodone N-oxide. In vivo, noroxycodone was formed as a major rat urinary metabolite from oxycodone N-oxide presumably after retro-reduction to oxycodone and oxidative -demethylation. To a lesser extent, oxycodone, noroxymorphone, and oxymorphone were observed as urinary metabolites. SIGNIFICANCE STATEMENT: This manuscript describes the -oxygenation of oxycodone in vitro as well as in small animals and humans. A new metabolite was quantified as oxycodone N-oxide. Oxycodone N-oxide undergoes extensive retro-reduction to oxycodone. This re-establishes the metabolic profile of oxycodone and introduces new concepts about a metabolic futile cycle related to oxycodone metabolism.
Topics: Analgesics, Opioid; Animals; Cytochrome P-450 Enzyme System; Female; Hemoglobins; Humans; Male; Mixed Function Oxygenases; Morphinans; NADP; Oxides; Oxycodone; Oxymorphone; Rats
PubMed: 31727673
DOI: 10.1124/dmd.119.089300 -
Pharmacogenomics Mar 2017Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects... (Observational Study)
Observational Study
AIM
Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism.
METHODS
30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM).
RESULTS
Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for C, p = 0.016 for AUC and p = 0.026 for AUC). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for C, p = 0.001 for AUC and p = 0.004 for AUC).
CONCLUSION
CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.
Topics: Administration, Oral; Adolescent; Analgesics, Opioid; Child; Child, Preschool; Cytochrome P-450 CYP2D6; Female; Humans; Male; Oxycodone; Pain, Postoperative; Pharmacogenetics; Pilot Projects; Prospective Studies
PubMed: 28244808
DOI: 10.2217/pgs-2016-0183 -
Journal of Managed Care & Specialty... May 2020Oxymorphone's metabolism does not involve the hepatic cytochrome P450 (CYP) system. The effect of this pharmacokinetic feature of oxymorphone on opioid prescribing is...
BACKGROUND
Oxymorphone's metabolism does not involve the hepatic cytochrome P450 (CYP) system. The effect of this pharmacokinetic feature of oxymorphone on opioid prescribing is unknown.
OBJECTIVE
To assess the relative frequency with which oxymorphone and oxycodone (a CYP3A-metabolized opioid analgesic) were each prescribed to patients concomitantly receiving CYP3A-modifying drugs (i.e., inducers and inhibitors) to characterize opioid-prescribing patterns in patients at risk for CYP3A-related drug interactions.
METHODS
We analyzed the Sentinel Distributed Database from January 1, 2013, to December 31, 2016, to identify the proportion of patients with concomitant dispensing of selected CYP3A modifiers among initiators of oxymorphone. We then repeated the analysis using oxycodone instead of oxymorphone. We conducted sensitivity analyses that varied the washout periods for each opioid to account for potential opioid switching.
RESULTS
In the primary analysis, the proportion of patients with concomitant incident dispensings of oxymorphone and selected CYP3A modifiers was 3.26% (95% CI = 3.09%-3.43%), and the proportion of patients with incident dispensings of oxycodone and selected CYP3A modifiers was 2.82% (95% CI = 2.79%-2.85%). The difference between proportions was 0.43% (95% CI = 0.26%-0.60%). Sensitivity analyses that varied the washout periods for each opioid with respect to the other opioid to account for switching yielded similar results.
CONCLUSIONS
We observed similar proportions of patients using selected CYP3A modifiers concomitantly with both oxymorphone and oxycodone. While the CIs of the point estimates did not overlap, the absolute differences between the proportions were small.
DISCLOSURES
This project was supported by Task Order HHSF22301001T under Master Agreement HHSF223201400030I from the U.S. Food and Drug Administration (FDA). The FDA approved the study protocol, including the statistical analysis plan, and reviewed and approved the manuscript. Coauthors from the FDA participated in the results interpretation and in the preparation and decision to submit the manuscript for publication. Coyle, Money, Staffa, Meyer, and Woods are employed by the FDA. The other authors have no financial conflicts of interest to report. The views expressed are those of the authors and not necessarily those of the U.S. Department of Health and Human Services, U.S. Food and Drug Administration.
Topics: Adverse Drug Reaction Reporting Systems; Analgesics, Opioid; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Oxycodone; Oxymorphone; Pain, Intractable; Practice Patterns, Physicians'; United States
PubMed: 32347183
DOI: 10.18553/jmcp.2020.26.5.668 -
Scientific Reports Sep 2023Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them,...
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.
Topics: Humans; Early Detection of Cancer; Histone Deacetylase 6; Bexarotene; Oxymorphone; Immunotherapy; Blood Group Antigens; Neoplasms
PubMed: 37660065
DOI: 10.1038/s41598-023-41325-9 -
Anesthesiology Oct 2020The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary... (Review)
Review
The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.
Topics: Advisory Committees; Analgesics; Analgesics, Opioid; Anesthetics; Congresses as Topic; Decision Making; Delayed-Action Preparations; Drug Approval; Humans; Opioid-Related Disorders; Oxymorphone; Spiro Compounds; Thiophenes; United States
PubMed: 32773684
DOI: 10.1097/ALN.0000000000003485