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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 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 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 -
Drug and Alcohol Dependence Jun 2020Our objective was to describe trends and deaths in young children associated with opioid analgesics.
BACKGROUND
Our objective was to describe trends and deaths in young children associated with opioid analgesics.
METHODS
Analysis of pediatric exposures using the RADARS System Poison Center Program from July 1, 2010 through December 31, 2018. Cases involving a child < 6 years, with an exposure to one or more opioids: buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tramadol. Poisson regression was used to model the shape of the time response curve.
RESULTS
48,560 cases were identified, median age 2 years (IQR 1.4, 2.0), 52.4 % male. The most commonly involved opioid was hydrocodone (32.5 %); buprenorphine and methadone had the highest exposure rates when adjusted for dispensed prescriptions (0.84 and 0.73 per 10,000 prescriptions). There were 28 deaths, methadone being the most commonly involved opioid (16). Exposures decreased significantly accounting for population (from 8.39 to 4.19 exposures per 100,000 children) and per prescription (from 0.33 to 0.25 exposures per 10,000 prescriptions). After adjustment for prescriptions, the exposure rate for hydromorphone and fentanyl increased over the study period, while buprenorphine had the greatest decrease in exposure rate. Among 28 deaths, 11 (39 %) were known or suspected to have been exposed, but medical care was not sought or was delayed.
CONCLUSION
Pediatric opioid exposure rates by prescription and population decreased from July 2010 through December 2018. However, with over 48,000 exposures and 28 deaths, the opioid epidemic continues to impact young children. Many exposures including deaths were preventable. Continued improvements in prevention require a multifaceted approach.
Topics: Analgesics, Opioid; Buprenorphine; Child, Preschool; Epidemics; Female; Fentanyl; Humans; Infant; Male; Methadone; Morphine; Opioid Epidemic; Oxycodone; Poison Control Centers; Prescription Drugs
PubMed: 32178937
DOI: 10.1016/j.drugalcdep.2020.107924 -
The Hastings Center Report Jan 2020I first became aware of bioethics in the spring of 1980. I had spent a thirty-six-hour shift shadowing a medical resident, and I was struck that many of the resident's...
I first became aware of bioethics in the spring of 1980. I had spent a thirty-six-hour shift shadowing a medical resident, and I was struck that many of the resident's decisions had ethical dimensions. The next day, I came across the Hastings Center Report, and I realized I wanted to explore ethical issues I found implicit in clinical care, even though I still wanted to become a pediatrician. In September 2019, when I attended my first meeting of the U.S. Food and Drug Administration's Pediatric Advisory Committee, as a pediatric pulmonologist, I had the same sense of awe and curiosity that I had forty years ago. What had appeared initially as somewhat technical decisions about the regulation of drug labeling was suffused with ethical questions. The committee was asked to discuss possible changes to the labeling of two previously approved drugs.
Topics: Acetates; Advisory Committees; Bioethics; Cyclopropanes; Drug Labeling; Humans; Oxymorphone; Pediatrics; Quinolines; Sulfides; United States; United States Food and Drug Administration
PubMed: 32068277
DOI: 10.1002/hast.1074 -
Toxicology in Vitro : An International... Jun 2020Multiple cases of potentially life-threatening thrombotic microangiopathy (TMA) have resulted from intravenous abuse of medications containing polyethylene oxide (PEO),...
Development of an in vitro system and model-based translational framework to assess haemolysis risk following intravenous abuse of medications containing polyethylene oxide.
Multiple cases of potentially life-threatening thrombotic microangiopathy (TMA) have resulted from intravenous abuse of medications containing polyethylene oxide (PEO), most often Opana ER (oxymorphone hydrochloride extended release). No validated models are available to assess the risk of TMA with different formulations and extraction methods following intravenous abuse. We have developed an in vitro system that involves passing pooled blood containing the excipient of interest through a syringe needle and assessing haemolysis via haemoglobin release. Haemolysis is induced by high shear stress caused by the flow of blood containing PEO through a narrow-bore syringe needle, recapitulating the mechanism in small blood vessels. Using the in vitro system, we demonstrate that high-molecular-weight PEO (>1 MDa) induces haemolysis in a concentration-dependent manner under flowing but not static conditions. We use data from the in vitro system and published in vivo data to predict the time course of the haemolytic response in vivo via a pharmacometric model. The in vitro system is a novel method for investigating factors influencing PEO-induced haemolysis. In combination with our model-based translational framework, the in vitro system allows straightforward assessment of the haemolytic potential of PEO-containing medications, and may find application in gauging TMA risk following intravenous abuse.
Topics: Animals; Cells, Cultured; Erythrocytes; Excipients; Guinea Pigs; Hemoglobins; Hemolysis; Humans; Models, Biological; Polyethylene Glycols; Risk; Substance Abuse, Intravenous
PubMed: 31958510
DOI: 10.1016/j.tiv.2020.104776 -
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 -
Biopharmaceutics & Drug Disposition Feb 2020Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play...
Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug-drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3-4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4-4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.
Topics: Computer Simulation; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Gene Expression Regulation, Enzymologic; Humans; Models, Biological; Oxycodone; Software
PubMed: 31925778
DOI: 10.1002/bdd.2215 -
Journal of Analytical Toxicology May 2020A comparative analysis of enzyme-linked immunosorbent assay (ELISA) and quadrupole time-of-flight mass spectrometry (LC-QTOF) for the detection of opioids in blood...
A comparative analysis of enzyme-linked immunosorbent assay (ELISA) and quadrupole time-of-flight mass spectrometry (LC-QTOF) for the detection of opioids in blood samples is presented. The Orange County Crime Lab (OCCL) was concerned that the opioid drug class was not accurately detected at low concentrations due to the use of LC-QTOF as a non-targeted screening method for multiple classes of drugs. In order to investigate this issue, 968 ante-mortem and postmortem blood samples were analyzed by ELISA for the presence of the following opioids: morphine, morphine-glucuronide, codeine, codeine-glucuronide, hydrocodone, hydromorphone, hydromorphone-glucuronide, oxycodone, oxymorphone and oxymorphone-glucuronide. All samples had been previously analyzed by LC-QTOF. Overall, 84 samples tested positive for opioids. Discrepant samples between ELISA and LC-QTOF were analyzed by a liquid chromatography tandem mass spectrometry confirmation method in order to determine the true composition of the sample. Upon review of the discrepant samples, no forensically relevant concentration of opioids was missed by LC-QTOF. Thus, the ability of the OCCL's LC-QTOF screening method was verified to detect opioids at low concentrations.
Topics: Analgesics, Opioid; Chromatography, Liquid; Codeine; Enzyme-Linked Immunosorbent Assay; Humans; Hydrocodone; Hydromorphone; Morphine; Morphine Derivatives; Oxycodone; Oxymorphone; Substance Abuse Detection
PubMed: 31897469
DOI: 10.1093/jat/bkz109 -
Patterns in opioid prescription in the United States by region and prescribers over a 4-year period.Journal of Opioid Management 2019As determinants of the opioid epidemic are several, describing patterns of opioid prescription over time is of importance.
BACKGROUND
As determinants of the opioid epidemic are several, describing patterns of opioid prescription over time is of importance.
OBJECTIVE
To characterize the prescribing patterns of opioids per US region and physician specialty from 2012 to 2015.
METHODS
Truven Health Analytics MarketScan® Databases were used to obtain data on opioid prescription rates per US region and physician specialty for the years 2012-2015. Opioids included in the study are tramadol, hydrocodone, codeine, oxycodone, oxymorphone, methadone, and fentanyl.
RESULTS
Starting sample consisted of 5,860,096 individuals. An increase in prescriptions was seen for codeine (22.3 percent), oxycodone (22.4 percent), and tramadol (22.4 percent), while other opioids had decreases between 6.5 and 20.2 percent during this period. Family medicine physicians were the most frequent prescriber for all opioids except for oxycodone; nonphysician prescribers' share of prescriptions nearly doubled for all opioids. The share of oxycodone and of tramadol among all opioids increased in all regions, while the opposite was seen for hydrocodone. Codeine prescription share increased substantially in the South but not in other regions. When comparing the period of 2012-2015, differences were significant for all regions (p < 0.0001 for all regions). In 2015, the rate of prescription of oxycodone was nearly twofold higher in the Northeast vs North Central (38 percent vs 18.5 percent, p < 0.0001), while tramadol was substantially more frequently prescribed in the South, where it responded to nearly 20 percent of all opioid prescriptions (p < 0.0001).
CONCLUSION
Patterns of prescription per opioid vary considerably per physician specialty and per US region. Although an overall decrease in prescriptions was seen, certain opioids were more frequently prescribed in 2015 than in 2012.
Topics: Analgesics, Opioid; Drug Prescriptions; Humans; Hydrocodone; Oxycodone; Practice Patterns, Physicians'; Tramadol; United States
PubMed: 31850512
DOI: 10.5055/jom.2019.0541