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Psychopharmacology Dec 2022Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like...
RATIONALE
Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial μ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway.
OBJECTIVES
Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020).
METHODS
Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride.
FINDINGS
Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related.
CONCLUSIONS
Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.
Topics: Animals; Rats; Analgesics, Opioid; Mitragyna; Oxycodone; Plant Extracts; Receptors, Opioid; Secologanin Tryptamine Alkaloids
PubMed: 36308562
DOI: 10.1007/s00213-022-06244-z -
Journal of Clinical Pharmacology Apr 2017Oxycodone DETERx (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended-release, microsphere-in-capsule, abuse-deterrent formulation designed to retain its... (Randomized Controlled Trial)
Randomized Controlled Trial
Oxycodone DETERx (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended-release, microsphere-in-capsule, abuse-deterrent formulation designed to retain its extended-release properties after tampering (eg, chewing/crushing). This randomized, double-blind, placebo-controlled, triple-dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate-release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high-fat, high-calorie meal and fasted), chewed oxycodone DETERx (high-fat, high-calorie meal and fasted), crushed immediate-release oxycodone (fasted), and placebo (high-fat, high-calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty-eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate-release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (E ) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .01). The time to E was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate-release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate-release oxycodone.
Topics: Administration, Oral; Adolescent; Adult; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Drug Compounding; Female; Humans; Male; Mastication; Middle Aged; Opioid-Related Disorders; Oxycodone; Young Adult
PubMed: 27669664
DOI: 10.1002/jcph.833 -
Bioengineered Apr 2022Endothelial dysfunction is an important mechanism involved in myocardial ischemia-reperfusion (I/R) injury. We aimed to explore the effects of Oxycodone on myocardial...
Endothelial dysfunction is an important mechanism involved in myocardial ischemia-reperfusion (I/R) injury. We aimed to explore the effects of Oxycodone on myocardial I/R injury in vivo and in vitro to reveal its mechanisms related to Sigma-1 Receptor (SIGMAR1). A rat model of I/R-induced myocardial injury was developed. The ischemic area and myocardial histopathological changes after oxycodone addition were evaluated by TTC staining and H&E staining. LDH, CK-MB and cTnI levels were used to assess myocardial function. Then, the endothelial integrity was reflected by the expressions of ZO-1, Claudin-1 and Occludin. Afterward, ELISA, RT-qPCR, western blot and immunofluorescence assays were adopted for the detection of inflammation-related genes. SIGMAR1 expression in myocardial tissues induced by I/R and cardiac microvascular endothelial cells (CMECs) under hypoxic/reoxygenation (H/R) was determined using RT-qPCR and western blotting. Subsequently, after SIGMAR1 silencing or BD1047 addition (a SIGMAR1 antagonist), cell apoptosis and endothelial integrity were analyzed in the presence of Oxycodone in H/R-stimulated CMECs. Results indicated that Oxycodone decreased the ischemic area and improved myocardial function in myocardial I/R injury rat. Oxycodone improved myocardial histopathological injury and elevated endothelial integrity, evidenced by upregulated ZO-1, Claudin-1 and Occludin expressions. Moreover, inflammatory response was alleviated after Oxycodone administration. Molecular docking suggested that SIGMAR1 could directly bind to Oxycodone. Oxycodone elevated SIGMAR1 expression and SIGMAR1 deletion or BD1047 addition attenuated the impacts of Oxycodone on apoptosis and endothelial integrity of CMECs induced by H/R. Collectively, Oxycodone alleviates myocardial I/R injury in vivo and in vitro by binding to SIGMAR1.
Topics: Animals; Apoptosis; Claudin-1; Endothelial Cells; Molecular Docking Simulation; Myocardial Reperfusion Injury; Myocytes, Cardiac; Occludin; Oxycodone; Rats; Receptors, sigma; Sigma-1 Receptor
PubMed: 35412431
DOI: 10.1080/21655979.2022.2057632 -
British Journal of Clinical Pharmacology Feb 2017This prospective study aimed to characterize the population pharmacokinetics of intravenous oxycodone and to determine the minimum effective concentration (MEC) and... (Clinical Trial)
Clinical Trial
AIMS
This prospective study aimed to characterize the population pharmacokinetics of intravenous oxycodone and to determine the minimum effective concentration (MEC) and minimum effective analgesic concentration (MEAC) of oxycodone for major open intra-abdominal surgery.
METHODS
In the pharmacokinetic study, patients were administered intravenous oxycodone (0.1 mg kg ), and arterial blood was sampled at pre-set intervals. In the analgesic-potency study, patients were administered intravenous oxycodone (0.1 mg kg ) 30 min before the end of the surgery, were placed in the postoperative anaesthesia care unit (PACU), and were asked to rate their pain every 10 min using a visual analogue scale (0 = no pain, 10 = most severe pain). On the first occasion that wound pain at rest and during compression was rated as ≥3 or ≥5, respectively, the first blood sample was obtained to determine the MEC. A second blood sample was obtained after titration with 2 mg of oxycodone to yield wound pain <3 at rest and <5 during wound compression, and MEAC was determined. MEC and MEAC were determined again in each patient.
RESULTS
In the population pharmacokinetic study (n = 54), oxycodone plasma concentration over time was well described by a three-compartment mammillary model. Lean body mass and age were significant covariates for the volume of distribution and metabolic clearance of the pharmacokinetic model of oxycodone, respectively. The analgesic-potency study (n = 50) showed that the median (95% CI) MEC and MEAC were 31.5 (19.2-42.8) and 74.1 (29.2-128.3) ng ml (first measurements) and 63.4 (15.6-120.1) and 76.1 (32.9-132.7) ng ml (second measurements), respectively.
CONCLUSIONS
In major intra-abdominal open surgery, the MEAC and analgesic potency of oxycodone were 75 ng ml and 60 ng ml , respectively.
Topics: Abdomen; Administration, Intravenous; Aged; Analgesics, Opioid; Female; Humans; Male; Middle Aged; Models, Biological; Oxycodone; Pain Measurement; Pain, Postoperative; Prospective Studies
PubMed: 27558774
DOI: 10.1111/bcp.13101 -
Paediatric Anaesthesia Dec 2021Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic...
BACKGROUND
Oxycodone is used in children and adults for the control of acute postoperative pain. Covariate influences such as age, size, and fat mass on oxycodone pharmacokinetic parameters over the human lifespan are poorly quantified.
METHODS
Pooled oxycodone time-concentration profiles were available from preterm neonates to adults. Data from intravenous, intramuscular, buccal, and epidural formulations were analyzed using nonlinear mixed-effects models. Normal fat mass was used to determine the influence of fat on oxycodone pharmacokinetics. Theory-based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A maturation function described the increase in clearance in neonates and infants.
RESULTS
There were 237 subjects (24 weeks postmenstrual age to 75 years; 0.44-110 kg) providing 1317 plasma concentrations. A three-compartment model with first-order elimination best described oxycodone disposition. Population parameter estimates were clearance (CL) 48.6 L.h .70 kg (CV 71%); intercompartmental clearances (Q2) 220 L.h .70 kg (CV 64%); Q3 1.45 L.h .70 kg ; volume of distribution in the central compartment (V1) 98.2 L.70 kg (CV 76%); rapidly equilibrating peripheral compartment (V2) 90.1 L. 70 kg (CV 76%); slow equilibrating peripheral compartment (V3) 28.9 L.70 kg . Total body weight was the best size descriptor for clearances and volumes. Absorption halftimes (T ) were: 1.1 minutes for intramuscular, 70 minutes for epidural, 82 minutes for nasogastric, and 159.6 minutes for buccal administration routes. The relative bioavailability after nasogastric administration was 0.673 with a lag time of 8.7 minutes.
CONCLUSIONS
Clearance matured with age; 8% of the typical adult value at 24 weeks postmenstrual age, 33% in a term neonate and reached 90% of the adult clearance value by the end of the first year of life. Allometric scaling using total body weight was the better size descriptor of oxycodone clearance than fat-free mass.
Topics: Administration, Intravenous; Adult; Child; Humans; Infant; Infant, Newborn; Metabolic Clearance Rate; Models, Biological; Nonlinear Dynamics; Oxycodone; Pain, Postoperative
PubMed: 34469607
DOI: 10.1111/pan.14283 -
PloS One 2020To evaluate the efficacy, safety and cost-effectiveness of Oxycodone Hydrochloride Controlled-release Tablets (CR oxycodone) and Morphine Sulfate Sustained-release... (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVE
To evaluate the efficacy, safety and cost-effectiveness of Oxycodone Hydrochloride Controlled-release Tablets (CR oxycodone) and Morphine Sulfate Sustained-release Tablets (SR morphine) for moderate to severe cancer pain titration.
METHODS
Randomized controlled trials meeting the inclusion criteria were searched through Medline, Cochrane Library, Pubmed, EMbase, CNKI,VIP and WanFang database from the data of their establishment to June 2019. The efficacy and safety data were extracted from the included literature. The pain control rate was calculated to eatimate efficacy. Meta-analysis was conducted by Revman5.1.4. A decision tree model was built to simulate cancer pain titration process. The initial dose of CR oxycodone and SR morphine group were 20mg and 30mg respectively. Oral immediate-release morphine was administered to treat break-out pain. The incremental cost-effectiveness ratio was performed with TreeAge Pro 2019.
RESULTS
19 studies (1680 patients)were included in this study. Meta-analysis showed that the pain control rate of CR oxycodone and SR morphine were 86% and 82.98% respectively. The costs of CR oxycodone and SR morphine were $23.27 and $13.31. The incremental cost-effectiveness ratio per unit was approximate $329.76. At the willingness-to-pay threshold of $8836, CR oxycodone was cost-effective, while the corresponding probability of being cost-effective at the willingness-to-pay threshold of $300 was 31.6%. One-way sensitivity analysis confirmed robustness of results.
CONCLUSIONS
CR oxycodone could be a cost-effective option compared with SR morphine for moderate to severe cancer pain titration in China, according to the threshold defined by the WHO.
Topics: Cancer Pain; Cost-Benefit Analysis; Decision Trees; Delayed-Action Preparations; Economics, Pharmaceutical; Humans; Morphine; Oxycodone; Publication Bias; Risk; Treatment Outcome
PubMed: 32302346
DOI: 10.1371/journal.pone.0231763 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2020N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is...
N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N-demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible-light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup.
Topics: Analgesics; Demethylation; Humans; Morphinans; Oxycodone
PubMed: 31898822
DOI: 10.1002/chem.201905505 -
Journal of Pharmaceutical Sciences Aug 1991The permeability of hairless mouse skin membrane to the weak base narcotic analgesic oxycodone (pKa = 8.53) was investigated. The effects of pH on the solubility and...
The permeability of hairless mouse skin membrane to the weak base narcotic analgesic oxycodone (pKa = 8.53) was investigated. The effects of pH on the solubility and skin permeation rate were also studied. The results of the study of skin permeation of drug through hairless mouse skin suggest that the permeability of oxycodone base is approximately 7.4 times higher than that of protonated oxycodone. The nonionic species of oxycodone, at various drug loadings, was then incorporated in a Dow-Corning silicone elastomer for the evaluation of the release rate and skin permeation rate. It was found that Q/t1/2 is directly proportional to the square root of the drug loading dose, as expected by Higuchi's equation (where Q is the cumulative amount released and t is time). However, the skin permeation rate was observed to increase initially with drug loading and level off at the loading dose of 60 mg/cm3.
Topics: Administration, Cutaneous; Animals; Chromatography, High Pressure Liquid; Diffusion; Drug Delivery Systems; Half-Life; Hydrogen-Ion Concentration; In Vitro Techniques; Mice; Mice, Hairless; Oxycodone; Silicone Elastomers; Skin Absorption
PubMed: 1791532
DOI: 10.1002/jps.2600800806 -
Journal of Managed Care Pharmacy : JMCP 2003Although use of long-acting opioid analgesics has increased for chronic nonmalignant pain management, little is known about patient-reported utilization patterns.
BACKGROUND:
Although use of long-acting opioid analgesics has increased for chronic nonmalignant pain management, little is known about patient-reported utilization patterns.
OBJECTIVES:
To assess patient-reported utilization patterns of fentanyl transdermal system and oxycodone hydrochloride (HCl) controlled-release among patients with chronic nonmalignant pain and to compare these patterns to standard dose administration guidelines recommended in the manufacturers' prescribing information (PI).
METHODS:
Cross-sectional, observational, multicenter study of English-speaking patients who were seeking chronic nonmalignant pain management from 6 outpatient pain clinics. The inclusion criteria for the study were (1) diagnosis of chronic nonmalignant pain, (2) prescription for and current use of either transdermal fentanyl or oxycodone HCl controlled-release, and (3) duration of use for either transdermal fentanyl or oxycodone HCl controlled-release of at least 6 weeks. Patients completed either an oxycodone HCl controlled-release or transdermal fentanyl utilization questionnaire. A conversion table was used to standardize opioid analgesic doses from transdermal fentanyl or oxycodone HCl controlled-release to daily oral morphine equivalents. The principal outcome measures were the average interval between oxycodone HCl controlled-release administrations, the number of days the current transdermal fentanyl patch would be worn, and the percentage of oxycodone HCl controlled-release and transdermal fentanyl patients whose administration frequency exceeded the standard recommendation in the manufacturer's PI (every 12 hours for oxycodone HCl controlled-release or every 72 hours for transdermal fentanyl). Other outcome measures included the number of oxycodone HCl controlled-release tablets per administration, the daily dose of long-acting opioid, the duration of adequate pain relief, and the difference in daily oral morphine equivalents between transdermal fentanyl and oxycodone HCl controlled-release patients, after adjusting in a multivariate regression model for demographic and clinical characteristics.
RESULTS:
A total of 690 patients were enrolled in this study; 437 (63.4%) received oxycodone HCl controlled- release and 253 (36.6%) received transdermal fentanyl. Oxycodone HCl controlled-release patients reported taking a median of 1 tablet 3 times per day or a median of 3 tablets per day. A mean of 1.6 tablets per administration and 4.6 tablets per day were taken. The average interval between administrations of oxycodone HCl controlled-release was 7.8 hours, and the median daily dose was 80.0 mg (mean 155.6 mg). Among oxycodone HCl controlled-release patients, 17.5% had an average interval between administrations of 12 or more hours, whereas 1.9% reported the duration of pain relief as 12 or more hours. Transdermal fentanyl patients reported wearing the patch, on average, for 2.5 days (median 2.5), and 41.2% reported wearing the patch for at least 3 days, whereas 14.1% reported the duration of pain relief as at least 3 days. The median daily dosage strength of transdermal fentanyl was 75.0 mcg/hour. In the multivariate regression analysis, oxycodone HCl controlled-release patients had, on average, roughly 22 mg additional oral morphine equivalents per day relative to transdermal fentanyl patients (not statistically significant); the probability that oxycodone HCl controlled-release patients had higher oral morphine equivalents was 82.6%, which suggests a trend toward higher oral morphine equivalents per day in the oxycodone HCl controlled-release group.
CONCLUSIONS:
Transdermal fentanyl and oxycodone HCl controlled-release both appear to be used by patients in a manner that is inconsistent with the standard recommendation in the manufacturers' PI; however, the difference between patient-reported utilization and the PI recommendation is more pronounced with oxycodone HCl controlled-release.
Topics: Analgesics, Opioid; Delayed-Action Preparations; Female; Fentanyl; Humans; Male; Oxycodone; Pain
PubMed: 14613448
DOI: 10.18553/jmcp.2003.9.5.457 -
Pharmacogenetics and Genomics Oct 2018
Topics: Analgesics, Opioid; Humans; Metabolic Networks and Pathways; Oxycodone; Pharmacogenetics
PubMed: 30222708
DOI: 10.1097/FPC.0000000000000351