Doses Of Oxycodone Research Articles

Do CYP2D6 genotypes affect oxycodone dose, pharmacokinetics, pain, and adverse effects in cancer?

To examine the associations between CYP2D6 and CYP3A4 polymorphisms, plasma oxycodone and metabolite concentrations, and oxycodone response (dose, pain scores, and adverse effects) in people with pain from advanced cancer. This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects), and blood (pharmacokinetics, DNA). Negative binomial regression and logistic regression were used. Within 33 participants, there were no differences in oxycodone response between CYP2D6 intermediate/poor metabolisers compared to normal metabolisers.Higher plasma noroxycodone and noroxycodone/oxycodone concentration ratios had higher odds of uncontrolled average pain (OR 2.44 (95%CI 1.00-5.95), p = 0.05 and OR 10.48 (95%CI 1.42-77.15), p = 0.02, respectively). There was no observed benefit in CYP2D6 genotyping in oxycodone response, however monitoring noroxycodone and oxymorphone concentrations warrant further examination.

At-home Administration of Opioid Analgesia in Children After Reduction of Forearm Fracture.

Controversy exists surrounding which agents best provide analgesia in children with fractures. Prior studies have demonstrated that ED visits for fracture-related pain have the highest rates of opioid prescribing. Studies have also found that NSAIDs are equivalent at controlling acute fracture-related pain. In a time when one must balance the risk of inadequate pain control with potential opioid misuse, providers have little data to guide them in terms of the best recommendations for adequate pain control at home. This prospective observational study investigates parental pain management practices after ED discharge for children who underwent a forearm fracture reduction. Surveys filled out by parents were used to gather data on the proportion of children discharged with an opioid prescription, the number of doses of opioid that were administered after discharge, and parental satisfaction with their child's pain control. We analyzed data for 61 patients who completed the postdischarge survey. Of these, 62% received a prescription for oxycodone at discharge, and 50% used at least 1 dose of oxycodone at home. The median number of doses administered at home, 1.5 (IQR, 0-3), was significantly lower than the number of doses of oxycodone prescribed, 10 (IQR, 5-12) (P < 0.001). Parents reported a high level of satisfaction with the medications received at discharge with nearly all ranging between 4 (satisfied) and 5 (very satisfied) (median, 5; IQR, 4-5). No significant difference was detected in the satisfaction between families who received a prescription for oxycodone at discharge (median, 5; IQR, 4-5) and those who did not (median, 5; IQR, 4-5) (P = 0.28). We observed a large range in the number of doses of oxycodone prescribed at discharge and a significant difference between the number of doses being prescribed and those being used by families. A prescription of 2 doses of oxycodone would be sufficient to treat postreduction pain in the majority of children.

The Role of Acid-Sensing Ion Channel 1A (ASIC1A) in the Behavioral and Synaptic Effects of Oxycodone and Other Opioids.

Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a-/- mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a-/- mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a-/- mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies.

Safety and efficacy of oxycodone for refractory dyspnea in end-stage heart failure patients with chronic kidney disease: a case series of eight patients

BackgroundMorphine is effective in palliative care for patients with end-stage heart failure; however, its use is avoided in patients with impaired renal function because it tends to induce adverse effects. Although oxycodone has been reported to be a useful alternative, the evidence is insufficient. Therefore, we investigated the safety and efficacy of oxycodone in eight patients with end-stage heart failure complicated by chronic kidney disease. MethodsThis single-center retrospective study reviewed patients with end-stage heart failure who were referred to the heart failure multidisciplinary team at our institution and administered oxycodone for refractory dyspnea during hospitalization between January 2011 and December 2018. We examined the details of oxycodone usage, vital signs, and the Modified Borg Scale (MBS), which quantifies the symptoms of dyspnea and adverse events.ResultsOxycodone was administered for refractory dyspnea in eight patients with end-stage heart failure [mean age: 81 years, men: 4, New York Heart Association functional class IV: 8, median left ventricular ejection fraction: < 40% (n = 6) and ≥ 50% (n = 2)]. Renal function was reduced in all patients; the estimated glomerular filtration rate (eGFR) in seven patients was < 30 mL/min/1.73 m2. The median initial intravenous dose of oxycodone was 7.05 mg/day (range: 5–10 mg/day), and the average duration of administration was 15.8 days. Significant decreases in MBS (before: median 9, range 7–10 vs. after: median 2.5, range 1–8; p < 0.01) were observed at a median of 2.0 days (range: 2 h to 7 days) after beginning oxycodone administration. Systolic blood pressure, heart rate, and respiratory rate were not significantly altered after treatment. Adverse events, including constipation, nausea, and tremors, were observed in three patients. However, no lethal adverse events related to oxycodone treatment occurred during treatment.ConclusionsThis study revealed the clinical practice of oxycodone treatment and suggested that it is an alternative therapy as a viable palliative for refractory dyspnea in patients with end-stage heart failure who should avoid the use of morphine.

A retrospective study of duloxetine for phantom limb pain post lower‐limb amputation

AbstractBackgroundPhantom limb pain (PLP) refers to the painful sensory perception of a missing limb after amputation, which can have physical and psychological impacts.AimTo determine the effectiveness of duloxetine for pain management in PLP by the reduction of opioid doses and other neuropathic analgesics when introduced into multimodal pain management strategies in the subacute rehabilitation setting.MethodThis was a retrospective observational case‐matched cohort study of patients who were admitted to a geriatric and rehabilitation unit at a tertiary Australian hospital from January 2005–December 2017 with PLP after lower‐limb amputation. Patients were included if they had a new amputation and experienced PLP. The primary outcome was a difference in oxycodone dose equivalents at discharge between the two cohorts. Univariable analysis was used to compare groups. Ethical approval was granted by the Metro South Low Negligible Risk Ethics Committee (Reference no: LNR/2018/QMS/47370) and the study conforms with the National statement on ethical conduct in human research.ResultsThirty patients from the duloxetine treatment cohort and 57 patients from the non‐duloxetine cohort were identified. Participants were predominantly male (81%) and had a median age of 63 years (interquartile range = 10.7). Both populations showed a similar rate of opioid dose reduction comparing doses at admission with those at discharge. There were no significant differences in absolute oxycodone equivalent doses at the two observed check points: admission and discharge.ConclusionThis study demonstrated that opioid consumption in post‐surgical lower‐limb amputees reporting PLP was not significantly different between populations that used and did not use duloxetine. Future research should evaluate the efficacy of duloxetine in PLP pain management using a multisite prospective study design.

Is Opioid Consumption Impacted by Study Participation? Maintenance of Fewer Opioid Refills With Reduced Prescription Quantity After Posterior Spinal Fusion in Adolescents With Idiopathic Scoliosis.

Opioid overprescribing can lead to nonmedical opioid use. In a previous prospective study (STUDY), we showed that a standardized protocol involving preoperative education and reduced opioid prescription quantity decreased opioid use in idiopathic scoliosis patients following posterior spinal fusion (PSF). A potential limitation was the Hawthorne effect, where participant behavior changes due to observation. At STUDY conclusion, we continued the reduced opioid prescriptions but discontinued the formal preoperative education. This retrospective study (post-STUDY) assessed if opioid refill requests increased outside of a study setting. Post-STUDY included patients aged 10 to 17 years who underwent PSF for idiopathic scoliosis between January 2022 and December 2023 and were discharged with a prescription of ≤30 oxycodone doses. Patients were excluded if they had previous spine surgery or were discharged with an opioid other than oxycodone. Demographics, perioperative variables, and opioid refill requests were compared with the data from STUDY, in which patients were aware their opioid use would be tracked. Patient-reported outcomes were collected via Scoliosis Research Society-22r (SRS-22r) surveys. The post-STUDY cohort included 67 patients (69% female). The average age at the time of PSF was 13.9 years (range, 11 to 17y). The mean number of levels fused was slightly higher (10.9 vs. 10.0, P=0.04), and intraoperative estimated blood loss was lower (211 vs. 303mL, P<0.01) compared with the STUDY cohort. Demographics, preoperative major curve magnitude, surgery duration, and length of hospital stay were similar. The percentage of patients who requested and received opioid refills between the post-STUDY and STUDY cohorts was also similar [6/67 (9%) vs. 3/49 (6%), P=0.30]. SRS-22r showed improvements in self-image, satisfaction, and mean total score from preoperative to postoperative. Reduced opioid prescriptions did not result in increased opioid refill requests in adolescents undergoing PSF for idiopathic scoliosis outside of a study setting. While formal preoperative discussions about postoperative pain control are important, other factors likely influence opioid use. Further research should explore characteristics that predispose patients to require higher amounts of postoperative opioids. Level III-therapeutic.

Naldemedine-induced perforation of a diverticulum in the sigmoid colon of a patient with opioid-related constipation: a case report

BackgroundNaldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine.Case presentationThe patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated.ConclusionsThese results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints.

PKMζ alters oxycodone-taking in a dose- and sex-dependent manner

Opioid use disorder involves disruptions to glutamate homeostasis and dendritic spine density in the reward system. PKMζ is an atypical isoform of protein kinase C that is expressed exclusively in neurons and plays a role in postsynaptic glutamate signaling and dendritic spine maturation. As opioid use leads to alterations in glutamate transmission and dendritic spine density, we hypothesized that PKMζ deletion would alter opioid-taking behaviors. The current study examined two doses of oxycodone self-administration in male and female mice with constitutive deletion of PKMζ compared to wildtype controls. At a dose of 0.25 mg/kg/infusion, PKMζ deletion significantly potentiated oxycodone self-administration in both male and female mice. However, increases in motivation for oxycodone, as indicated by increased breakpoint on a progressive ratio schedule, were only seen in male PKMζ knockout mice and not females. When we examined a lower dose of oxycodone, 0.125 mg/kg/infusion, PKMζ knockout led to increases in oxycodone self-administration only in female mice. Additionally, female PKMζ knockout mice exhibited higher breakpoints on a progressive ratio schedule at this dose compared to all other groups. In addition to the self-administration studies, we also examined locomotor sensitization in response to experimenter administered oxycodone. PKMζ KO decreased oxycodone induced locomotion in males and potentiated oxycodone sensitization in females. Together, these results suggest that PKMζ acts to dampen oxycodone taking in both sexes, but females may be more sensitive to its effects.

Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial.

Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Inbred rat heredity and sex affect oral oxycodone self-administration and augmented intake in long sessions: correlations with anxiety and novelty-seeking.

Oxycodone abuse begins with prescription oral oxycodone, yet vulnerability factors determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1,4,16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p< 0.001). Each sex increased intake during 16-h vs 4-h sessions (p<2e-16), but a subset of strains dramatically augmented intake at 16-h (p=0.0005). Heritability (h 2) of active licks/4-h at increasing oxycodone dose ranged from 0.30-0.53. Under a progressive ratio schedule, breakpoints were strain-dependent (p<2e-16). Cued reinstatement was greater in females (p<0.001). Naive rats were assessed by elevated plus maze (EPM), open field (OF) and novel object interaction (NOI). We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and pleiotropic genes affect anxiety and multiple SA parameters.

Ageing and Polypharmacy in Mesenchymal Stromal Cells: Metabolic Impact Assessed by Hyperspectral Imaging of Autofluorescence.

The impact of age on mesenchymal stromal cell (MSC) characteristics has been well researched. However, increased age is concomitant with increased prevalence of polypharmacy. This adjustable factor may have further implications for the functionality of MSCs and the effectiveness of autologous MSC procedures. We applied hyperspectral microscopy of cell autofluorescence-a non-invasive imaging technique used to characterise cytometabolic heterogeneity-to identify changes in the autofluorescence signals of MSCs from (1) young mice, (2) old mice, (3) young mice randomised to receive polypharmacy (9-10 weeks of oral therapeutic doses of simvastatin, metoprolol, oxycodone, oxybutynin and citalopram), and (4) old mice randomised to receive polypharmacy. Principal Component Analysis and Logistic Regression Analysis were used to assess alterations in spectral and associated metabolic characteristics. Modelling demonstrated that cells from young mice receiving polypharmacy had less NAD(P)H and increased porphyrin relative to cells from old control mice, allowing for effective separation of the two groups (AUC of ROC curve > 0.94). Similarly, cells from old polypharmacy mice were accurately separated from those from young controls due to lower levels of NAD(P)H (p < 0.001) and higher porphyrin (p < 0.001), allowing for an extremely accurate logistic regression (AUC of ROC curve = 0.99). This polypharmacy regimen may have a more profound impact on MSCs than ageing, and can simultaneously reduce optical redox ratio (ORR) and increase porphyrin levels. This has implications for the use of autologous MSCs for older patients with chronic disease.

Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice

Rationale/ObjectivesTargeting cannabinoid receptor type 1 (CB1R) has shown promise for treating opioid withdrawal symptoms. This study aimed to investigate the efficacy of a specific CB1R negative allosteric modulator (NAM), Org27569, in reducing both naloxone-precipitated and protracted withdrawal symptoms in oxycodone-dependent mice.MethodsMice received escalating doses of oxycodone (9–33 mg/kg IP) or saline twice daily for 9 days, followed by a final dose of oxycodone (33 mg/kg) or saline in the morning of day 9. In one cohort, the impact of Org27569 (3, 10, and 30 mg/kg) on naloxone (10 mg/kg IP) precipitated withdrawal symptoms was assessed. In another cohort, Org27569 (3 mg/kg) effects on the acquisition of conditioned place aversion to naloxone (0.6 mg/kg) precipitated opioid withdrawal, on behaviour following a 7–9-day abstinence period, and on naloxone (0.6 mg/kg) precipitated withdrawal-induced escape behaviour in a novel assay were assessed.ResultsAlthough Org27569 decreased opioid withdrawal-induced jumping at doses of 10 and 30 mg/kg, these effects were confounded by reduced locomotion. At all doses tested, Org27569 had a modest inhibitory effect on gastrointestinal motility. At the lower dose of 3 mg/kg, which was not confounded by locomotor effects, Org27569 did not impact naloxone-precipitated withdrawal-induced jumping, acquisition of oxycodone withdrawal-induced conditioned place aversion, or naloxone-precipitated withdrawal-induced escape behaviour in a novel assay. A clear protracted opioid withdrawal phenotype was not observed in assays of anxiety-like or social behaviour.ConclusionsOrg27569 effects on negative affective-like symptoms were confounded by locomotor effects and effects on gastrointestinal motility were not opioid withdrawal specific. Further studies are needed in a model that produces a more pronounced protracted withdrawal syndrome.

Multisite prospective study of perioperative pain management practices for anterior cruciate ligament reconstruction in adolescents: Society for Pediatric Anesthesia Improvement Network (SPAIN) Project Report

IntroductionAlthough 200 000 adolescents undergo anterior cruciate ligament reconstruction (ACLR) surgery annually, no benchmarks for pediatric post-ACLR pain management exist. We created a multicenter, prospective, observational registry to describe pain...

Breast milk oxycodone concentrations in mothers given oxycodone for post-Caesarean delivery pain management.

Both effective analgesia and early breastfeeding play an important role in maternal and neonatal well-being after Caesarean delivery. We studied controlled-release oxycodone tablet treatment for postoperative pain management and determined the excretion of oxycodone into breast milk. Controlled-release oxycodone/naloxone 10/5-mg tablets (n = 21) or controlled-release oxycodone 10-mg tablets (n = 22) were administered to mothers twice a day for the first 3days after elective Caesarean delivery as a part of multimodal analgesia. Maternal plasma and breast milk samples were collected daily. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed with ultra-performance liquid chromatography-mass spectrometry. Maternal pain intensity was recorded with an 11-point Numeric Rating Scale (0-10). Neonatal oxycodone exposure was estimated by simulating five different exposure scenarios, including the highest possible exposure through breast milk. The mean oxycodone and noroxycodone milk-to-maternal plasma ratios were 3.2 and 3.0, respectively. A strong correlation was found between plasma and breast milk oxycodone (R2 = 0.87) and noroxycodone concentrations (R2 = 0.91). In the simulated highest neonatal exposure scenario, the neonate's maximum plasma concentration was estimated to be 5.4ng/mL and the estimated weight-adjusted infant oxycodone dose was less than 10% of the maternal dose. Pain intensities were similarly low between the two treatment groups. The oxycodone dose received from colostrum and breast milk during the first three postoperative days after Caesarean delivery is assumed safe for healthy, term neonates, but in extreme cases it is possible for the neonate to receive a dose through breast milk that may elicit opioid effects.

A Multicenter Retrospective Observational Study Analyzing the Effect of Polypharmacy on Oxycodone Tolerability

Polypharmacy is becoming increasingly troublesome in the treatment of cancer. The aim of this study was to explore the effects of concomitant polypharmacy comprising drugs that inhibit CYP3A4 and/or CYP2D6 on the oxycodone tolerability in patients with cancer. We conducted a multicenter retrospective study encompassing 20 hospitals. The data used for the study were obtained during the first 2 wk of oxycodone administration. The incidence of oxycodone discontinuation or dose reductions due to side effects and oxycodone-induced nausea and vomiting (OINV) were compared between patients not treated with either inhibitor and those treated with concomitant CYP3A4 or CYP2D6 inhibitors. The incidence of oxycodone discontinuation or dose reductions in patients treated with ≥3 concomitant CYP2D6 inhibitors (18.2%) tended to be higher than that in patients without this treatment (8.2%; p = 0.09). Moreover, the incidence of OINV in patients treated with 2 concomitant CYP3A4 inhibitors (29.8%) was significantly higher than that in patients without this treatment (15.5%; p = 0.049). Multivariate analysis showed that more than two concomitant CYP3A4 inhibitors and no concomitant use of naldemedine were independent risk factors for OINV. Concomitant polypharmacy involving CYP3A4 inhibitors increases the risk of OINV. Therefore, medications concomitantly used with oxycodone should be optimized.

Assessment of feasibility of opioid-free anesthesia combined with preoperative thoracic paravertebral block and postoperative intravenous patient-controlled analgesia oxycodone with non-opioid analgesics in the perioperative anesthetic management for video-assisted thoracic surgery.

This study, conducted between December 2015 and March 2018 at a single university hospital, explored the feasibility and safety of opioid-free anesthesia combined with preoperative thoracic paravertebral block (ThPVB) for patients undergoing elective video-assisted thoracoscopic surgery (VATS). The aim was to assess the impact of this approach on postoperative pain levels and opioid consumption. Sixty-four patients scheduled for elective VATS were randomly assigned to either the intervention group, receiving opioid-free anesthesia with ThPVB, or the control group, managed with standard general anesthesia. Postoperatively, both groups received oxycodone patient-controlled analgesia along with non-opioid analgesics. Pain intensity was measured using the Numeric Pain Rating Scale (NRS) and Prince Henry Hospital Pain Score (PHHPS). The total dose of postoperative oxycodone and the occurrence of opioid-related adverse events were recorded during the 24-hour follow-up period. Patients in the intervention group showed significantly lower pain levels at 20 and 24 hours post-procedure ( P = 0.015, P = 0.021, respectively) compared to the control group. Notably, oxycodone consumption at 24 hours was significantly higher in the control group ( p < 0.0001). No serious adverse events were observed during the study period. This study demonstrates the feasibility and safety of opioid-free anesthesia combined with ThPVB for elective VATS. The approach significantly reduces postoperative pain and the need for opioids, supporting its potential as an effective and balanced perioperative anesthetic strategy.

Analysis of postoperative pulmonary complications after gastrectomy for gastric cancer: development and validation of a nomogram.

Postoperative pulmonary complications (PPCs) are common in gastric cancer patients after gastrectomy. The aim of our study was to investigate the perioperative risk factors and to develop a nomogram to identify patients who are at significant risk of PPCs. The clinical data of gastric cancer patients who underwent elective gastrectomy in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were retrospectively collected. All patients were randomly divided into a training and a validation cohort at a ratio of 7:3. Univariate and multivariate analysis were applied to identify the independent risk factors that might predict PPCs, and a nomogram was constructed. Both discrimination and calibration abilities were estimated by the area under a receiver operating characteristic curve (AUC) and calibration curves. The clinical effectiveness of the nomogram was further quantified with the decision curve analysis (DCA). Of 2,124 included patients, one hundred and fifty patients (7.1%) developed PPCs. Binary logistic analysis showed that age > 65 years, higher total cholesterol level, longer duration of surgery, total gastrectomy, and the dose of oxycodone > 5.5 mg were independent risk factors for the occurrence of PPCs, which were contained in the nomogram. The predictive nomogram showed good discrimination and calibration [an AUC of 0.735 (95% CI: 0.687-0.783) in a training cohort and 0.781 (95% CI: 0.715-0.847) in a validation cohort]. The calibration curve and decision curve analysis showed a good agreement between nomogram predictions and actual observations. We developed a nomogram model based on age, total cholesterol, extent of resection, duration of surgery, and the dose of oxycodone to predict the risk of PPCs in gastric cancer patients after elective gastrectomy.

The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism

This study aimed to investigate the interactions between icotinib/apatinib and oxycodone in rats and to unveil the underlying mechanism. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine oxycodone and its demethylated metabolite simultaneously. In vivo, Sprague–Dawley (SD) male rats were administered oxycodone with or without icotinib or apatinib. Blood samples were collected and subjected to UPLC-MS/MS analysis. An enzyme incubation assay was performed to investigate the mechanism of drug–drug interaction using both rat and human liver microsomes (RLM and HLM). The results showed that icotinib markedly increased the AUC(0–t) and AUC(0–∞) of oxycodone but decreased the CLz/F. The Cmax of oxycodone increased significantly upon co-administration of apatinib. In vitro, the Km value of oxycodone metabolism was 101.7 ± 5.40 μM and 529.6 ± 19.60 μM in RLMs and HLMs, respectively. Icotinib and apatinib inhibited the disposition of oxycodone, with a mixed mechanism in RLM (IC50 = 3.29 ± 0.090 μM and 0.95 ± 0.88 μM, respectively) and a competitive and mixed mechanism in HLM (IC50 = 22.34 ± 0.81 μM and 0.48 ± 0.05 μM, respectively). In conclusion, both icotinib and apatinib inhibit the metabolism of oxycodone in vitro and in vivo. Therefore, the dose of oxycodone should be reconsidered when co-administered with icotinib or apatinib.

Behavioral mechanisms of oxycodone's effects in female and male rats: Reinforcement delay and impulsive choice.

μ-Opioid agonists (e.g., morphine) typically increase impulsive choice, which has been interpreted as an opioid-induced increase in sensitivity to reinforcement delay. Relatively little research has been done with opioids other than morphine (e.g., oxycodone), or on sex differences in opioid effects, on impulsive choice. The present study investigated the effects of acute (0.1-1.0 mg/kg) and chronic (1.0 mg/kg twice/day) administration of oxycodone on choice controlled by reinforcement delay, a primary mechanism implicated in impulsive choice, in female and male rats. Rats responded under a concurrent-chains procedure designed to quantify the effects of reinforcement delay on choice within each session. For both sexes, choice was sensitive to delay under this procedure. Sensitivity to delay under baseline was slightly higher for males than females, suggesting more impulsive choice with males. When given acutely, intermediate and higher doses of oxycodone decreased sensitivity to delay; this effect was larger and more reliable in males than females. When given chronically, sex differences were also observed: tolerance developed to the sensitivity-decreasing effects in females, whereas sensitization developed in males. These data suggest that reinforcement delay may play an important role in sex differences in impulsive choice, as well as in the effects of acute and chronic administration of opioids in impulsive choice. However, drug-induced changes in impulsive choice could be related to at least two potential behavioral mechanisms: reinforcement delay and/or reinforcement magnitude. Effects of oxycodone on sensitivity to reinforcement magnitude remain to be fully characterized. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018mg/kg/injection). Once trained, cocaine (0.018mg/kg/injection) or oxycodone (0.0056mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1-3.2µg/kg/injection), nalfurafine (0.0032-0.1µg/kg/injection), triazole 1.1 (3.2-100.0µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.