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British Journal of Clinical Pharmacology Apr 2017This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and... (Clinical Trial)
Clinical Trial
AIMS
This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year-old infants.
METHODS
Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg kg during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified. The unconjugated forms of these compounds were determined in urine collected after up to 24 or 48 h from 25 infants. Pharmacokinetics was determined using noncompartmental analysis and reported for six clinically relevant age groups based on postmenstrual age.
RESULTS
Oxycodone pharmacokinetics changed markedly with patient age. Preterm neonates were found to have the highest pharmacokinetic variability out of the study population. In extremely preterm neonates (n = 6) median of elimination half-life was 8.8 h (range 6.8-12.5), in preterm (n = 11) 7.4 h (4.2-11.6), and in older neonates (n = 22) 4.1 h (2.4-5.8), all of which were significantly longer than that in infants aged 6-24 months (n = 12) 2.0 h (1.7-2.6). Median renal clearance was fairly constant in all age groups, whereas non-renal clearance markedly increased with age. Noroxycodone was the major metabolite in plasma and urine.
CONCLUSIONS
Oxycodone elimination is slower and pharmacokinetic variability more pronounced in neonates when compared to older infants. These findings highlight the importance of careful dose titration for neonates.
Topics: Age Factors; Analgesics, Opioid; Child, Preschool; Female; Half-Life; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Infant, Premature; Male; Morphinans; Oxycodone; Prospective Studies; Time Factors
PubMed: 27780305
DOI: 10.1111/bcp.13164 -
Addiction Biology Mar 2022Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have...
Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc) and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the blood oxygen level dependent (BOLD) response, and that intra-hemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional magnetic resonance imaging (MRI) measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.
Topics: Animals; Brain Concussion; Drug-Seeking Behavior; Neuroimaging; Oxycodone; Rats; Self Administration
PubMed: 35229952
DOI: 10.1111/adb.13134 -
Japanese Journal of Clinical Oncology Jun 2018Hydromorphone is a standard opioid analgesic for cancer pain that, prior to this study, was not approved in Japan, where options for opioid switching are limited. We... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized, double-blind, non-inferiority study of hydromorphone hydrochloride immediate-release tablets versus oxycodone hydrochloride immediate-release powder for cancer pain: efficacy and safety in Japanese cancer patients.
BACKGROUND
Hydromorphone is a standard opioid analgesic for cancer pain that, prior to this study, was not approved in Japan, where options for opioid switching are limited. We aimed to investigate the efficacy and safety of hydromorphone (DS-7113b) immediate-release tablets in opioid-naïve cancer patients with moderate to severe cancer pain.
METHODS
Multicenter, active-controlled, randomized, double-blind, parallel-group, non-inferiority study of 183 cancer patients over 20 years of age at 50 clinical sites in Japan. Hydromorphone tablets or oxycodone hydrochloride powder was orally administered four times daily for 5 days. The initial doses of hydromorphone and oxycodone hydrochloride were 4 mg/day and 10 mg/day, respectively, and adjusted as necessary. Efficacy was evaluated as the intergroup difference (95% confidence interval [CI]) of the least squares mean by analysis of covariance, using the baseline visual analog scale (VAS) as a covariate for change in VAS score at treatment completion/discontinuation in the full analysis set.
RESULTS
Non-inferiority of hydromorphone versus oxycodone was confirmed, with an intergroup difference (95% CI) in the least squares mean of -3.4 mm (-9.8 to 3.1 mm) for change in VAS scores, which was below the upper limit of the 95% CI at 10 mm, the non-inferiority limit determined during study planning. Adverse events occurred in 83.0% (73/88) of patients in the hydromorphone group and 77.4% (65/84) in the oxycodone group. The most frequently observed adverse events were somnolence, constipation, vomiting and nausea.
CONCLUSIONS
The efficacy and safety of hydromorphone tablets are equivalent to those of oxycodone immediate-release powder.
Topics: Aged; Analgesics, Opioid; Asian People; Cancer Pain; Delayed-Action Preparations; Demography; Depression; Double-Blind Method; Female; Humans; Hydromorphone; Japan; Male; Neoplasms; Oxycodone; Pain Measurement; Powders; Tablets; Treatment Outcome
PubMed: 29659913
DOI: 10.1093/jjco/hyy038 -
Annals of Palliative Medicine Jan 2021Opioid titration is the best way to achieve a balance of pain relief and tolerable side effects for moderate-to-severe cancer pain. Rapid dose titration helps to achieve... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Opioid titration is the best way to achieve a balance of pain relief and tolerable side effects for moderate-to-severe cancer pain. Rapid dose titration helps to achieve early analgesia. We explored the efficacy and safety of a 12-hour rapid dose titration in treating cancer pain.
METHODS
Opioid-naïve patients with moderate-to-severe cancer pain were randomly divided into oxycodone group and morphine group. The medicines were adjusted to oxycodone sustained-release tablets after 12 hours, and the dose of oxycodone sustained-release tablets was adjusted every 12 hours. The analgesic efficacy and adverse reactions during the treatment were observed until the 72nd hour.
RESULTS
A total of 106 patients were included in the analysis, with 51 patients in the oxycodone group and 55 in the morphine group. The pain control rate of all patients reached 96.2% 24 hours after treatment, and it was not significantly different between two groups (P=0.619). The proportion of Numeric Rating Scale (NRS) score that decreased by ≥50% was significantly higher in the oxycodone group than in the morphine group (P=0.013). In the first 12 hours and 24 hours, significantly lower proportions of patients in the oxycodone group experienced multiple episodes of breakthrough pain (BTP) than in the morphine group (P=0.032, P=0.021, respectively). The quality of life of the patients in the oxycodone group was significantly higher than that in the morphine group at the 24th hour (P=0.047), as was the degree to which the quality of life had improved (P<0.001). Only grade 1 or 2 adverse reactions were observed during the study period, and no significant difference between two groups.
CONCLUSIONS
The 12-hour rapid dose titration method can achieve early analgesia, with mild adverse reactions. In particular, the rapid titration method with background sustained-release oxycodone can reduce BTP episodes and achieve significant early pain relief.
Topics: Analgesics, Opioid; Cancer Pain; Humans; Morphine; Neoplasms; Oxycodone; Quality of Life
PubMed: 33474955
DOI: 10.21037/apm-20-2336 -
Drugs in R&D Jun 2016Oxycodone is the mo st commonly used opioid for the treatment of moderate to severe pain. The peak cerebrospinal fluid concentration after epidural oxycodone was... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVES
Oxycodone is the mo st commonly used opioid for the treatment of moderate to severe pain. The peak cerebrospinal fluid concentration after epidural oxycodone was reported to be 300-fold greater (0.025 mM) than when administered intravenously after gynecologic surgery. Additionally, those patients administered epidural oxycodone had lower pain scores, needed less rescue analgesics and had fewer adverse effects compared with intravenous administration. However, oxycodone neurotoxicity requires evaluation before intrathecal implementation for routine clinical use.
METHODS
We used two in vitro cell culture models to compare the cytotoxicity of oxycodone with that of morphine, and to study the mechanisms underlying toxicity. Human neuroblastoma cells and mouse motoneuronal cells were treated with increasing concentrations (0.0125-2 mM) of oxycodone or morphine, and were harvested at 24, 48 or 96 h. Cell cultures were evaluated with 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide and resazurin reduction assays.
RESULTS
Both morphine and oxycodone decreased cell viability in a dose-dependent manner at concentrations between 0.5 and 2 mM. Morphine increased the number of apoptotic cells compared with oxycodone when assessed by flow cytometry, and transmission electron microscopy images revealed that exposure to both opioids evoked the appearance of numerous electron-dense, probable autophagic vacuoles in the cytoplasm of the cells.
CONCLUSIONS
Based on these results, it seems that the cytotoxicity of oxycodone in motoneuronal cells is similar to or less than that of morphine, and occurs only at concentrations above the peak clinical concentration in the cerebrospinal fluid after epidural administration.
Topics: Analgesics, Opioid; Animals; Cell Line; Cell Survival; Drug Therapy, Combination; Flow Cytometry; Humans; Mice; Morphine; Motor Neurons; Neuroblastoma; Neurotoxicity Syndromes; Oxycodone
PubMed: 26913723
DOI: 10.1007/s40268-016-0125-0 -
Pharmacology, Biochemistry, and Behavior Oct 2021Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that mu-opioid-receptor-selective agonists, such as oxycodone, activate glia and increase the release of cytokines, causing a suppression of opioid-induced analgesic effects. Preclinical studies also show that certain medications, such as the broad-spectrum tetracycline antibiotic minocycline, inhibit opioid-induced glial activation and thereby enhance the analgesic effects of opioids. Importantly, minocycline reduces the rewarding effects of opioids at the same doses that it enhances opioid-induced analgesia.
AIMS
The purpose of the present study was to assess the effects of acute administration of minocycline on the subjective, physiological, and analgesic effects of oxycodone in human research volunteers.
DESIGN
This study was a within-subject, randomized, double-blind outpatient study. Participants completed five separate sessions in which they received 0, 100, or 200 mg minocycline (MINO) simultaneously with either 0 or 40 mg oxycodone (OXY). The subjective, physiological, and analgesic effects of OXY were measured before and repeatedly after drug administration.
SETTINGS AND PARTICIPANTS
Participants were between 21 and 45 years of age, non-treatment seeking, non-dependent recreational opioid users (N = 12). This study was conducted between 2013 and 2014 at the New York State Psychiatric Institute in New York, NY.
FINDINGS
MINO 100 and 200 mg were safe and well-tolerated in combination with OXY 40 mg. MINO 200 mg administered with OXY 40 mg attenuated OXY-induced positive subjective effects such as "Good Effect" and "Liking" compared to OXY alone. MINO did not alter the physiological or analgesic effects of OXY.
CONCLUSIONS
MINO may attenuate the abuse liability of mu-opioid-receptor-selective agonists.
Topics: Adult; Analgesia; Analgesics, Opioid; Anti-Bacterial Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Microglia; Middle Aged; Minocycline; New York; Opioid-Related Disorders; Oxycodone; Reward; Young Adult
PubMed: 34298029
DOI: 10.1016/j.pbb.2021.173241 -
Drugs in R&D Sep 2017Oxycodone is a semisynthetic opioid used for the treatment of moderate to severe pain. Two separate studies were conducted to assess the pharmacokinetic bioequivalence... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pharmacokinetic Bioequivalence Studies of an Extended-Release Oxycodone Hydrochloride Tablet in Healthy Japanese Subjects Under Fasting and Fed Conditions Without an Opioid Antagonist.
Oxycodone is a semisynthetic opioid used for the treatment of moderate to severe pain. Two separate studies were conducted to assess the pharmacokinetic bioequivalence of a newly formulated oxycodone hydrochloride extended-release tablet to a marketed oxycodone product in Japan under fasting and fed conditions. Each study was a randomized, open-label, single-dose, single-center, two-period, two-way crossover study. Healthy male Japanese subjects received the oxycodone 10-mg products under fasting and fed conditions. Blood samples were collected at specified time intervals, and plasma concentrations of oxycodone were analyzed using a validated liquid chromatography tandem mass spectrometry assay method. The pharmacokinetic parameters were determined via non-compartmental analysis. Pharmacokinetic metrics used for bioequivalence assessment were the maximum observed plasma concentration (C ) and the area under the concentration-time curve up to the last sampling time (AUC ). A total of 24 healthy subjects were enrolled in each study. One subject withdrew after completion of the first sequence under fed conditions. The ratios of geometric least square means for C and AUC under fasting conditions were 1.1110 (90% confidence interval [CI] 1.0562-1.1687) and 0.9946 (90% CI 0.9670-1.0231), respectively. The ratios of geometric least square means for C and AUC under fed conditions were 1.1417 (90% CI 1.0959-1.1895) and 1.0135 (90% CI 0.9810-1.0470), respectively. The 90% CIs were within the predefined range (0.80-1.25). Both treatments were well tolerated when taken without an opioid antagonist in healthy Japanese subjects. Pharmacokinetic bioequivalence between test and reference formulations under fasting and fed conditions was concluded in terms of both rate and extent of absorption.
Topics: Adult; Analgesics, Opioid; Area Under Curve; Chromatography, Liquid; Cross-Over Studies; Delayed-Action Preparations; Fasting; Food-Drug Interactions; Humans; Japan; Male; Oxycodone; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency; Young Adult
PubMed: 28516342
DOI: 10.1007/s40268-017-0184-x -
Drug and Alcohol Dependence Apr 2021The broad use/misuse of prescription opioids during pregnancy has resulted in a surge of infants with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability...
BACKGROUND
The broad use/misuse of prescription opioids during pregnancy has resulted in a surge of infants with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are its hallmarks, but the long-term consequences are unknown.
METHODS
A newly-developed preclinical model of oxycodone self-administration enables adult female rats to drink oxycodone (∼10/mg/kg/day) before and during pregnancy, and after delivery, and to maintain normal liquid intake, titrate dosing, and avoid withdrawal.
RESULTS
Oxycodone was detected in the serum of mothers and pups. Growth parameters in dams and pups and litter mass and size were similar to controls. There were no differences in paw retraction latency to a thermal stimulus between Oxycodone and Control pups at postnatal (PN) 2 or PN14. Oxycodone and Control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in Oxycodone pups relative to Control pups (p<0.031; Cohen's d=1.026). Finally, Oxycodone pups displayed withdrawal behaviors (p's<0.029; Cohen's d's>0.806), and Oxycodone males only vocalized more than Control pups in the first minute of testing (p's<0.050; Cohen's d's>.866). Significant effects were corroborated by estimation plots.
CONCLUSIONS
Our rat model of oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and sensory-motor behaviors. This preclinical model reproduces selective aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring.
Topics: Administration, Oral; Affect; Analgesics, Opioid; Animals; Animals, Newborn; Behavior, Animal; Communication; Disease Models, Animal; Female; Male; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Oxycodone; Pregnancy; Pregnancy Complications; Rats; Self Administration; Spatial Learning; Substance Withdrawal Syndrome
PubMed: 33761428
DOI: 10.1016/j.drugalcdep.2021.108628 -
MSystems Aug 2022Opioid drugs are commonly prescribed analgesic to pregnant women. Direct exposure to such drugs may slow gut motility, alter gut permeability, and affect the gut...
Opioid drugs are commonly prescribed analgesic to pregnant women. Direct exposure to such drugs may slow gut motility, alter gut permeability, and affect the gut microbiome. While such drugs affect gut microbiome in infants, no study to date has determined whether developmental exposure to such drugs results in longstanding effects on gut microbiota and correspondingly on host responses. We hypothesized developmental exposure to oxycodone (OXY) leads to enduring effects on gut microbiota and such changes are associated with adult neurobehavioral and metabolic changes. Female mice were treated daily with 5 mg OXY/kg or saline solution (control [CTL]) for 2 weeks prior to breeding and then throughout gestation. Male and female offspring pups were weaned, tested with a battery of behavioral and metabolic tests, and fecal boli were collected adulthood (120 days of age). In females, relative abundance of spp., Bacteroidetes, spp., TM7, spp., and Clostridia were greater in OXY versus CTL individuals. In males, relative abundance of Coriobacteriaceae, spp., spp., and Clostridia were elevated in OXY exposed individuals. Bacterial changes were also associated with predictive metabolite pathway alterations that also varied according to sex. In males and females, affected gut microbiota correlated with metabolic but not behavioral alterations. The findings suggest that developmental exposure to OXY leads to lasting effects on adult gut microbiota that might affect host metabolism, possibly through specific bacterial metabolites or other bacterial-derived products. Further work is needed to characterize how developmental exposure to OXY affects host responses through the gut microbiome. This is the first work to show in a rodent model that exposure to an opioid drug can lead to longstanding effects on the gut microbiota when examined at adulthood. Further, such bacterial changes are associated with metabolic host responses. Given the similarities between rodent and human microbiomes, it raises cause for concern that similar effects may become evident in children born to mothers taking oxycodone and other opioid drugs.
Topics: Humans; Adult; Child; Male; Female; Animals; Mice; Pregnancy; Gastrointestinal Microbiome; Oxycodone; Analgesics, Opioid; Microbiota; Social Behavior; Bacteria
PubMed: 35862801
DOI: 10.1128/msystems.00336-22 -
Addiction Biology Nov 2022A major obstacle in treating opioid use disorder is the persistence of drug seeking or craving during periods of abstinence, which is believed to contribute to relapse....
A major obstacle in treating opioid use disorder is the persistence of drug seeking or craving during periods of abstinence, which is believed to contribute to relapse. Dopamine transmission in the mesolimbic pathway is posited to contribute to opioid reinforcement, but the processes by which dopamine influences drug seeking have not been completely elucidated. To examine whether opioid seeking during abstinence is associated with alterations in dopamine transmission, female and male rats self-administered oxycodone under an intermittent access schedule of reinforcement. Following self-administration, rats underwent a forced abstinence period, and cue-induced seeking tests were conducted to assess oxycodone seeking. One day following the final seeking test, rats were sacrificed to perform ex vivo fast scan cyclic voltammetry and western blotting in the nucleus accumbens. Rats displayed reduced dopamine uptake rate on abstinence day 2 and abstinence day 15, compared to oxycodone-naïve rats. Further, on abstinence day 15, rats had reduced phosphorylation of the dopamine transporter. Additionally, local application of oxycodone to the nucleus accumbens reduced dopamine uptake in oxycodone-naïve rats and in rats during oxycodone abstinence, on abstinence day 2 and abstinence day 15. These observations suggest that abstinence from oxycodone results in dysfunctional dopamine transmission, which may contribute to sustained oxycodone seeking during abstinence.
Topics: Female; Male; Rats; Animals; Nucleus Accumbens; Oxycodone; Dopamine; Analgesics, Opioid; Drug-Seeking Behavior; Self Administration; Cocaine
PubMed: 36301217
DOI: 10.1111/adb.13241