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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 -
ENeuro 2021The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like... (Review)
Review
The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc.Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.
Topics: Animals; Behavior, Addictive; Biological Specimen Banks; Cocaine; Cocaine-Related Disorders; Oxycodone; Rats; Rats, Sprague-Dawley; Self Administration
PubMed: 33875455
DOI: 10.1523/ENEURO.0033-21.2021 -
Oxycodone-Related Deaths: The Significance of Pharmacokinetic and Pharmacodynamic Drug Interactions.European Journal of Drug Metabolism and... Mar 2022Oxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause...
BACKGROUND AND OBJECTIVES
Oxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause adverse effects or even fatal intoxication. The aims of this study were to investigate differences in prescriptions for and toxicological findings of pharmacodynamically and pharmacokinetically interacting drugs in fatal oxycodone-related intoxications and other causes of death. We also aimed to investigate the differences in prevalence of oxycodone prescriptions, and the detected postmortem oxycodone concentrations between fatal oxycodone-related intoxications and other causes of death.
METHODS
Forensic autopsy cases (2012-2018) where oxycodone was identified in femoral blood (n = 1236) were included. Medical history and prescription data were retrieved from national databases and linked to the forensic toxicology findings.
RESULTS
Oxycodone-related deaths were found to have higher blood concentrations of oxycodone (median 0.30 µg/g vs. 0.05 µg/g) and were less likely to have a prescription for oxycodone (OR 0.62) compared to nonintoxication deaths. Pharmacodynamically interacting drugs were prescribed in 79% and found in blood in 81% of the cases. Pharmacokinetically interacting drugs were rarely prescribed (1%). Oxycodone-related deaths were more likely to have prescriptions for a pharmacodynamically interacting drug (OR 1.7) and more often have co-findings of one or multiple pharmacodynamically interacting drugs (OR 5.6).
CONCLUSION
The results suggest that combined use of oxycodone and pharmacodynamically interacting drugs is associated with oxycodone-related death and that non-medical use of oxycodone is a potential risk factor for oxycodone-related intoxication.
Topics: Analgesics, Opioid; Databases, Factual; Drug Interactions; Forensic Toxicology; Oxycodone; Risk Factors
PubMed: 35025054
DOI: 10.1007/s13318-021-00750-9 -
Forensic Science International. Genetics Jul 2021Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine,...
Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.
Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Cytochrome P-450 CYP2D6; DNA Copy Number Variations; Female; Forensic Genetics; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Morphinans; Oxycodone; Pharmacogenomic Testing; Phenotype; Polymorphism, Single Nucleotide; Young Adult
PubMed: 33799050
DOI: 10.1016/j.fsigen.2021.102510 -
British Journal of Clinical Pharmacology Dec 2022The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials.
METHODS
Twenty-one healthy volunteers completed a cross-over trial with oxycodone (10 mg), tapentadol (50 mg) extended-release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post-interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory-evoked potential.
RESULTS
Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by -0.89 (P = .001, 95% confidence interval [CI] -1.46, -0.32), whereas oxycodone increased the latency of the N1 component of the sensory-evoked potential at the vertex by 12.5 ms (P = .003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P < .02), and the insula components moved caudally in both the oxycodone and tapentadol arms (all P < .03).
CONCLUSION
A decrease in the number of nociceptive withdrawal reflex was observed during tapentadol treatment, possibly relating to the noradrenaline reuptake inhibition effects on the spinal cord. Both oxycodone and tapentadol affected cortical measures possible due to μ-opioid receptor agonistic effects evident in the dipole sources, with the strongest effect being mediated by oxycodone. These findings could support the dual effect analgesic mechanisms of tapentadol in humans as previously shown in preclinical studies.
Topics: Humans; Tapentadol; Oxycodone; Phenols; Analgesics, Opioid; Spinal Cord; Brain; Electrophysiology; Double-Blind Method
PubMed: 35776835
DOI: 10.1111/bcp.15453 -
British Journal of Clinical Pharmacology Mar 2022Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas... (Randomized Controlled Trial)
Randomized Controlled Trial
Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas tapentadol also affects noradrenergic activity. However, knowledge about the function of the medications in the human brain is limited. The aim was to investigate effects of tapentadol and oxycodone on brain glutamate, the most important neurotransmitter in pain processing. Magnetic resonance spectroscopy was obtained in 21 healthy subjects from the anterior cingulate cortex, prefrontal cortex, and insula at baseline and after 14 days of treatment with either 50 mg tapentadol, 10 mg oxycodone (equipotent dose, both extended release) or placebo twice daily in a randomized double-blind cross-over study. Compared to baseline, decreased glutamate/creatine levels were identified in anterior cingulate cortex after tapentadol (1.26 ± 0.14 vs. 1.35 ± 0.18, P = .04) and oxycodone (1.26 ± 0.10 vs. 1.35 ± 0.12, P = .05) treatments, both with 7% reduction. This indicates that both analgesics modulate the glutamatergic system at the supraspinal level in humans.
Topics: Analgesics; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Glutamic Acid; Healthy Volunteers; Humans; Oxycodone; Phenols; Tapentadol
PubMed: 34427941
DOI: 10.1111/bcp.15050 -
British Journal of Clinical Pharmacology Oct 2017Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review... (Meta-Analysis)
Meta-Analysis Review
AIMS
Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant.
METHODS
We systematically reviewed the literature to September 11, 2016, to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale.
RESULTS
A total of 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified, as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and warfarin.
CONCLUSIONS
The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.
Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Ethanol; Humans; Injection Site Reaction; Morpholines; Nausea; Oxycodone; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Vomiting
PubMed: 28470980
DOI: 10.1111/bcp.13322 -
Addiction (Abingdon, England) Sep 2021To establish and quantify the association between abuse-deterrent formulation (ADF) oxycodone and 1-year risk of opioid-related harm.
AIM
To establish and quantify the association between abuse-deterrent formulation (ADF) oxycodone and 1-year risk of opioid-related harm.
DESIGN
Propensity score-matched cohort study of electronic medical records for years 2014-18, with patients followed up for 1 year after their index health-care visit.
SETTING
More than 70 million patients from 56 US health-care organizations.
PARTICIPANTS
Patients aged 18-64 years at index health-care visit with any indication for an oral opioid analgesic, with no past 12-month history of oral oxycodone use or substance use disorder, and who were alive at the end of the 1-year follow-up (new episode of prescription oral ADF oxycodone [OxyContin], n = 45 045; new episode of non-ADF oxycodone opioid preparation, n = 1 377 359).
MEASUREMENTS
International Classification of Diseases diagnoses of any opioid-related disorder or non-fatal opioid poisoning within 1 year of the index health-care visit. Pooled odds ratios (OR) with 95% confidence intervals (95% CI).
FINDINGS
After propensity score matching, 89 802 patients with a mean age of 44 [standard deviation (SD) = 11] years (62% women, 68% white) were included. During 1-year follow-up, 1445 diagnoses of opioid use disorder or opioid poisoning occurred in the ADF oxycodone cohort (34.8/1000 person-years) and 765 occurred in the non-ADF oxycodone cohort (18.2/1000 person-years). The odds of opioid-related adverse outcomes were increased in the ADF oxycodone cohort compared with the non-ADF oxycodone opioid cohort, including for opioid use disorders (OR = 2.02; 95% CI = 1.83, 2.23) and opioid poisoning (OR = 1.64 95% CI = 1.35, 1.99).
CONCLUSIONS
Patients with a new prescription of abuse-deterrent formulation oxycodone may be at increased risk of opioid-related harm.
Topics: Analgesics, Opioid; Child; Cohort Studies; Delayed-Action Preparations; Electronic Health Records; Female; Humans; Male; Opioid-Related Disorders; Oxycodone
PubMed: 33394528
DOI: 10.1111/add.15392 -
Pain Physician Feb 2017Opioids are the mainstay of pain management for acute postsurgical pain. Oral oxycodone is an opioid that can provide effective acute postoperative pain relief. (Review)
Review
BACKGROUND
Opioids are the mainstay of pain management for acute postsurgical pain. Oral oxycodone is an opioid that can provide effective acute postoperative pain relief.
OBJECTIVES
To evaluate the use of oral oxycodone for acute postoperative pain management.
STUDY DESIGN
This is a narrative review based on published articles searched in PubMed and Medline from 2003 to 2015 on oral oxycodone for acute postoperative pain management.
METHODS
Clinical trials related to the use of oral oxycodone for acute postoperative pain management were searched via PubMed and Medline from 2003 to 2015. The search terms used were "oral strong opioids," "postsurgical," "postoperative," "post-surgical," and "post-operative." Treatment interventions were compared for analgesic efficacy, rescue medication use, side effects, recovery, length of hospital stay, and patient satisfaction.
RESULTS
There were 26 clinical trials included in the review. Oral oxycodone showed superior postoperative analgesic efficacy compared with placebo in patients undergoing laparoscopic cholecystectomy, abdominal or pelvic surgery, bunionectomy, breast surgery, and spine surgery. When compared with intravenous opioids, oral oxycodone provided better or comparable pain relief following knee arthroplasty, spine surgery, caesarean section, laparoscopic colorectal surgery, and cardiac surgery. One study of dental postsurgery pain reported inferior pain control with oral oxycodone versus rofecoxib. (withdrawn from the US market due to cardiac safety concerns). In many studies, the demand for rescue analgesia and total opioid consumption were reduced in the oxycodone treatment arm. Patients receiving oral oxycodone experienced fewer opioid-related side effects than those on other opioids, and had a similar occurrence of postoperative nausea and vomiting as patients on placebo. Furthermore, oral oxycodone did not prolong hospital stay and was associated with lower drug costs compared with epidural and intravenous analgesics. Oxycodone administered as part of a multimodal analgesic regimen produced superior pain relief with fewer side effects and a reduced hospital stay.
LIMITATIONS
There is a limited number of randomized double blinded studies in individual surgical operations, thus making it more difficult to come up with definitive conclusions.
CONCLUSION
Oral oxycodone appears to offer safe and effective postoperative analgesia, and is a well-accepted and reasonable alternative to standard intravenous opioid analgesics.Key words: Postoperative, pain, analgesia, oral oxycodone, opioid.
Topics: Analgesia; Analgesics, Opioid; Clinical Trials as Topic; Female; Humans; Oxycodone; Pain Measurement; Pain, Postoperative; Pregnancy
PubMed: 28226340
DOI: No ID Found -
Pharmacology, Biochemistry, and Behavior Dec 2021Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This...
BACKGROUND
Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting.
METHODS
After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured.
RESULTS
One hundred twenty-eight adults (age 35-85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects.
CONCLUSION
Independent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alcohol Drinking; Analgesics, Opioid; Attention; Automobile Driving; Cognition; Ethanol; Female; Humans; Male; Memory, Short-Term; Middle Aged; Miosis; Oxycodone; Pain; Sex Factors; Surveys and Questionnaires
PubMed: 34742948
DOI: 10.1016/j.pbb.2021.173295