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Clinical Toxicology (Philadelphia, Pa.) Apr 2022Older adults are less likely than younger adults to receive naloxone therapy. Given high rates of prescription opioid use/misuse and increasing illicit opioid use among...
CONTEXT
Older adults are less likely than younger adults to receive naloxone therapy. Given high rates of prescription opioid use/misuse and increasing illicit opioid use among older adults, factors associated with naloxone administration for older opioid poisoning cases need examination.
METHODS
We analyzed the 83,135 opioid-involved cases aged 50+ from the 2015-2020 National Poison Data System. Single-variable logistic regression was used to examine associations of naloxone administration with demographic factors, exposure site/reason, medical outcomes, management site/level of care, clinical effects, and other interventions. Multivariable logistic regression models were fit to examine associations of naloxone administration with different types of opioids.
RESULTS
Over the six years, the proportion of prescription opioid cases that received naloxone therapy increased steadily from 21.9% to 28.4%. The proportion of illicit opioid cases that received naloxone therapy was 51.9% in 2015 and 59.8% in 2020 with a high of 64.4% in 2019. In 2020, the death rate for illicit opioid cases without naloxone therapy was 31.4% compared to 2.3% for those with the therapy. Cases managed at healthcare facilities (HCF) had higher odds of receiving naloxone therapy. Among prescription opioid cases, naloxone therapy rates among older and female cases and those managed at non-HCF settings were especially low even for major medical outcomes. Cases involving oxycodone, morphine, methadone, prescription fentanyl, hydromorphone, oxymorphone, and other/unknown opioids had higher odds of naloxone administration.
DISCUSSION
Rates of naloxone therapy for older prescription opioid poisoning cases need improvement. While rates were higher among illicit opioid cases, the drop in 2020 and the sharp increase in deaths among illicit opioid cases without naloxone therapy confirm the importance of access to this life-saving intervention.
CONCLUSIONS
Increased naloxone co-prescribing and other means of facilitating access to naloxone are needed to prevent opioid poisoning deaths among older adults who use prescription opioids.
Topics: Aged; Analgesics, Opioid; Female; Humans; Middle Aged; Naloxone; Opioid-Related Disorders; Poisons; Prescriptions
PubMed: 34554013
DOI: 10.1080/15563650.2021.1981362 -
Pharmaceutics Sep 2021Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by... (Review)
Review
Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor (). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy.
PubMed: 34575542
DOI: 10.3390/pharmaceutics13091466 -
Foods (Basel, Switzerland) Apr 2023The increase in bacterial resistance and the decline in the effectiveness of antimicrobial agents are challenging issues for the control of infectious diseases....
The increase in bacterial resistance and the decline in the effectiveness of antimicrobial agents are challenging issues for the control of infectious diseases. Traditional Chinese herbal plants are potential sources of new or alternative medicine. Here, we identified antimicrobial components and action modes of the methanol-phase extract from an edible herb Wight et Arn, which had a 68.18% inhibition rate against 22 species of common pathogenic bacteria. The extract was purified using preparative high-performance liquid chromatography (Prep-HPLC), and three separated fragments (Fragments 1-3) were obtained. Fragment 1 significantly elevated cell surface hydrophobicity and membrane permeability but reduced membrane fluidity, disrupting the cell integrity of the Gram-negative and Gram-positive pathogens tested ( < 0.05). Sixty-six compounds in Fragment 1 were identified using Ultra-HPLC and mass spectrometry (UHPLC-MS). The identified oxymorphone (6.29%) and rutin (6.29%) were predominant in Fragment 1. Multiple cellular metabolic pathways were altered by Fragment 1, such as the repressed ABC transporters, protein translation, and energy supply in two representative Gram-negative and Gram-positive strains ( < 0.05). Overall, this study demonstrates that Fragment 1 from Wight et Arn is a promising candidate for antibacterial medicine and food preservatives.
PubMed: 37107435
DOI: 10.3390/foods12081640 -
Clinical Drug Investigation Mar 2023While the current landscape of opioid use disorder (OUD) is complicated by the increase in use of non-prescription opioids, prescription opioids continue to be...
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.
Topics: Humans; Analgesics, Opioid; Oxycodone; Abuse-Deterrent Formulations; Cross-Sectional Studies; Oxymorphone; Opioid-Related Disorders; Delayed-Action Preparations
PubMed: 36859697
DOI: 10.1007/s40261-023-01248-9 -
Analytical Chemistry Jun 2020Oxycodone is a strong opioid frequently used as an analgesic. Although proven efficacious in the management of moderate to severe acute pain and cancer pain, use of...
Oxycodone is a strong opioid frequently used as an analgesic. Although proven efficacious in the management of moderate to severe acute pain and cancer pain, use of oxycodone imposes a risk of adverse effects such as addiction, overdose, and death. Fast and accurate determination of oxycodone blood concentration would enable personalized dosing and monitoring of the analgesic as well as quick diagnostics of possible overdose in emergency care. However, in addition to the parent drug, several metabolites are always present in the blood after a dose of oxycodone, and to date, there is no electrochemical data available on any of these metabolites. In this paper, a single-walled carbon nanotube (SWCNT) electrode and a Nafion-coated SWCNT electrode were used, for the first time, to study the electrochemical behavior of oxycodone and its two main metabolites, noroxycodone and oxymorphone. Both electrode types could selectively detect oxycodone in the presence of noroxycodone and oxymorphone. However, we have previously shown that addition of a Nafion coating on top of the SWCNT electrode is essential for direct measurements in complex biological matrices. Thus, the Nafion/SWCNT electrode was further characterized and used for measuring clinically relevant concentrations of oxycodone in buffer solution. The limit of detection for oxycodone with the Nafion/SWCNT sensor was 85 nM, and the linear range was 0.5-10 μM in buffer solution. This study shows that the fabricated Nafion/SWCNT sensor has potential to be applied in clinical concentration measurements.
Topics: Electrochemical Techniques; Electrodes; Fluorocarbon Polymers; Molecular Structure; Nanotubes, Carbon; Oxycodone; Particle Size; Surface Properties
PubMed: 32412733
DOI: 10.1021/acs.analchem.0c00450 -
Basic & Clinical Pharmacology &... Nov 2019The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the...
The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg bolus followed by continuous infusion of 0.05 mg·kg ·h for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg bolus followed by a 0.2 mg·kg bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL after infusion and 0.4 and 1.1 ng·mL after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.
Topics: Analgesia; Analgesics, Opioid; Animals; Brain Chemistry; Cerebellum; Cerebral Cortex; Female; Injections, Epidural; Models, Animal; Oxycodone; Oxymorphone; Pregnancy; Sheep; Spinal Cord; Thalamus; Tissue Distribution
PubMed: 31222944
DOI: 10.1111/bcpt.13276 -
Drug, Healthcare and Patient Safety 2019The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the...
BACKGROUND
The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the FDA through the MedWatch program. A significant number of adverse events reported in the FAERS database have been for opioid use. The objective of this study was to determine the frequency counts and associated deaths of opioid drug names in the FAERS database.
METHODS
Drug data were obtained from the DRUG and OUTCOME files in the database. Drugs identified included: morphine, fentanyl, oxycodone, hydrocodone, tramadol, hydromorphone, methadone, codeine, oxymorphone, meperidine, propoxyphene, diphenoxylate, and heroin. Frequency counts and concomitant deaths of opioid drug names were determined via the MySQL database management system.
RESULTS
Fifteen different opioid drugs identified in the FAERS database were associated with ADEs, including death, and 3 drugs (oxycodone, hydrocodone, fentanyl) accounted for more than half of the reports. The highest frequency count value was 158,181 for oxycodone, which represents approximately 20.2% of the frequency counts for the opioids. The lowest frequency count value was 2,161 for dextromethorphan, which represents approximately 0.3% of the total. The opioid with the highest proportion of deaths to drug count was heroin (71.8%), followed by dextromethorphan (55.6%), methadone (37.2%), morphine (26.8%), and propoxyphene (23.7%).
CONCLUSION
The FAERS database represents an important source for detection and reporting of adverse drug events (ADEs), in particular the opioids and related drugs. It remains a challenge to estimate the true incidence of ADEs for this class of drugs in the general population.
PubMed: 31695510
DOI: 10.2147/DHPS.S214771 -
Pain Jan 2022The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR),...
The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus cotreated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone antinociception in all models by 54.7% to 628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism, we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced antinociception using small molecule inhibitors (KN93 and Src-I1). Together, these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs through the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
Topics: Analgesics, Opioid; Animals; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Mice; Morphine; Receptors, Opioid, delta; Receptors, Opioid, mu
PubMed: 34252907
DOI: 10.1097/j.pain.0000000000002320 -
Current Drug Metabolism 2020Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, especially in the elderly population. Opioids, which are potent... (Meta-Analysis)
Meta-Analysis
Model-based Meta-analysis to Compare Primary Efficacy-endpoint, Efficacy-time Course, Safety, and Tolerability of Opioids Used in the Management of Osteoarthritic Pain in Humans.
BACKGROUND
Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, especially in the elderly population. Opioids, which are potent analgesics, have shown an extraordinary ability to reduce intense pain in many osteoarthritic clinical trials; however, there is an increased need for a study to integrate the reported outcomes and utilize them to achieve a better understanding. Herein, efficacy and safety aspects of opioids used to manage osteoarthritic pain were assessed and compared using a model-based meta-analysis (MBMA).
METHODS
To perform the analysis, a comprehensive database consisting of pain relief compounds with information on summary-level of efficacy over time, adverse events and dropout rates was compiled from multiple sources. MBMA was conducted using a nonlinear mixed-effects modeling approach.
RESULTS
The results of primary efficacy endpoint analysis indicated that the doses of oxycodone, oxymorphone, and tramadol required to produce 50% of the maximum effect were 47, 84, and 247 mg per day, respectively. Efficacytime course analysis showed that opioids had rapid time to efficacy onset, suggesting potentially powerful painrelieving effects. It was also found that gastrointestinal adverse events were the most opioid-associated and dosedependent adverse effects. In addition, the analysis revealed that opioids were well-tolerated at low to moderate doses.
CONCLUSION
This MBMA provides clinically meaningful insights into the efficacy and safety profiles of oxycodone, oxymorphone, and tramadol. Resultantly, the presented framework analysis can have an impact in the clinic on drug development where it can guide: the optimization of doses of opioids required to manage osteoarthritic pain; the making of precise key decisions for the positioning of new drugs, and; the design of more efficient trials.
Topics: Analgesics, Opioid; Humans; Models, Biological; Osteoarthritis; Oxycodone; Oxymorphone; Pain; Randomized Controlled Trials as Topic; Tramadol; Treatment Outcome
PubMed: 32407270
DOI: 10.2174/1389200221666200514130441 -
British Journal of Pharmacology Apr 2023Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health...
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.
Topics: Humans; Animals; Mice; Oxycodone; Oxymorphone; Cytochrome P-450 CYP3A; Benzodiazepines; Diazepam; Analgesics, Opioid; Models, Animal; Drug Overdose
PubMed: 34855983
DOI: 10.1111/bph.15765