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Nature Communications Dec 2023The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl leading to >70,000 overdose deaths annually; thus, new...
The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl leading to >70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, we present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Moreover, toxicokinetic evaluation in a repeat-dose rat study and human tissue cross-reactivity study reveals a favorable pharmacokinetic profile of CSX-1004 with no safety-related issues. Using a highly translational non-human primate (NHP) model of respiratory depression, we demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3-4 weeks. Furthermore, treatment with CSX-1004 produces up to a 15-fold potency reduction of fentanyl in NHP respiration, antinociception and operant responding assays without affecting non-fentanyl opioids like oxycodone. Taken together, our data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose.
Topics: Humans; Rats; Mice; Animals; United States; Analgesics, Opioid; Antibodies, Monoclonal; Fentanyl; Drug Overdose; Respiratory Insufficiency
PubMed: 38052779
DOI: 10.1038/s41467-023-43126-0 -
BMJ Open Oct 2023Postoperative pain is a main component influencing the recovery of patients with lung cancer. The combination of patient-controlled intravenous analgesia (PCIA) and...
Effect of oxycodone combined with ultrasound-guided thoracic paravertebral nerve block on postoperative analgesia in patients with lung cancer undergoing thoracoscopic surgery: protocol for a randomised controlled study.
INTRODUCTION
Postoperative pain is a main component influencing the recovery of patients with lung cancer. The combination of patient-controlled intravenous analgesia (PCIA) and paravertebral nerve block for postoperative analgesia in patients undergoing thoracoscopic lobectomy for lung cancer can achieve a satisfactory analgesic effect and promote early rehabilitation of patients. The objective is to investigate the optimal dose of oxycodone for PCIA combined with paravertebral nerve block, to achieve effective multimodal analgesia management in patients undergoing thoracoscopic lung cancer lobectomy.
METHODS AND ANALYSIS
This prospective, double-blind, single-centre, parallel-group, superiority study from 7 April 2023 to 31 December 2024 will include 160 participants scheduled for thoracoscopic lobectomy for lung cancer. Participants will be randomly assigned to four groups in a 1:1:1:1 ratio: OCA group (oxycodone: 0.5 mg/kg), OCB group (oxycodone: 1.0 mg/kg), OCC group (oxycodone: 1.5 mg/kg) and one sufentanil group (sufentanil: 2 µg/kg). Flurbiprofen 50 mg and ondansetron 16 mg are added to each group. All the drugs are diluted with 0.9% saline in a 100 mL volume, with a background infusion rate of 2 mL/hour, a bolus dose of 0.5 mL and a lockout interval of 15 min. The primary outcome is pain scores at rest and dynamic at 24 hours after surgery using a Numeric Rating Scale (NRS). Dynamic NRS scores are defined as NRS when coughing. NRS scores will be assessed at 2, 4, 12, 24 and 48 hours postoperatively. The secondary outcomes include the following variables: (1) NRS score at rest and dynamic at 2, 4, 12 and 48 hours postoperatively; (2) total dose of sufentanil or oxycodone consumption in PCIA; (3) the times of patient-controlled analgesia; (4) Ramsay Sedation Score (RSS) at 2, 4, 12, 24 and 48 hours after the surgery; (5) extubation time; (6) serum C-reactive protein and interleukin six levels; (7) incidence of postoperative nausea and vomiting; (8) incidence of itching; (9) incidence of respiratory depression and (10) gastrointestinal recovery (exhaust time).
ETHICS AND DISSEMINATION
The First Affiliated Hospital of Shandong First Medical University's Ethics Committee granted consent for this study (approval number: YXLL-KY-2022(116)). To enable widespread use of the data gathered, we plan to publish the trial's findings in an appropriate scientific journal after it is complete.
TRIAL REGISTRATION NUMBER
NCT05742256.
Topics: Humans; Oxycodone; Sufentanil; Prospective Studies; Thoracoscopy; Pain, Postoperative; Analgesia, Patient-Controlled; Nerve Block; Lung Neoplasms; Ultrasonography, Interventional; Analgesics, Opioid; Randomized Controlled Trials as Topic
PubMed: 37844986
DOI: 10.1136/bmjopen-2023-074416 -
Scientific Reports Aug 2023Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact...
Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.
Topics: Adult; Humans; Rats; Female; Male; Animals; Rats, Sprague-Dawley; Oxycodone; Analgesics, Opioid; Estrous Cycle; Reward
PubMed: 37626154
DOI: 10.1038/s41598-023-40971-3 -
CMAJ : Canadian Medical Association... Jul 2023Oxycodone is increasingly prescribed for postpartum analgesia in lieu of codeine owing to concerns regarding the neonatal safety of codeine during lactation. We examined...
BACKGROUND
Oxycodone is increasingly prescribed for postpartum analgesia in lieu of codeine owing to concerns regarding the neonatal safety of codeine during lactation. We examined whether initiation of oxycodone after delivery was associated with an increased risk of persistent opioid use relative to initiation of codeine.
METHODS
We conducted a population-based cohort study of people who filled a prescription for either codeine or oxycodone within 7 days of discharge from hospital after delivery between Sept. 1, 2012, and June 30, 2020. The primary outcome was persistent opioid use, defined as 1 or more additional prescriptions for an opioid within 90 days of the first postpartum prescription and 1 or more additional prescriptions in the 91 to 365 days thereafter. We used inverse probability of treatment weighting to assess the risk of persistent postpartum opioid use, comparing people who initiated oxycodone with those who initiated codeine.
RESULTS
Over the 8-year study period, we identified 70 607 people who filled an opioid prescription within 7 days of discharge from hospital: 21 308 (30.2%) received codeine and 49 299 (69.8%) oxycodone. Compared with people who filled a prescription for codeine, receipt of oxycodone was not associated with persistent opioid use (relative risk [RR] 1.04, 95% confidence interval [CI] 0.91-1.20). We found an association between a prescription for oxycodone and persistent use after vaginal delivery (RR 1.63, 95% CI 1.31-2.03), but not after cesarean delivery (RR 0.85, 95% CI 0.73-1.00).
INTERPRETATION
Initiation of oxycodone (v. codeine) was not associated with an increased risk of persistent opioid use, except after vaginal delivery.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Codeine; Oxycodone; Analgesics, Opioid; Cohort Studies; Retrospective Studies; Opioid-Related Disorders; Drug Prescriptions
PubMed: 37524396
DOI: 10.1503/cmaj.221351 -
Pain Reports Dec 2023Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and...
INTRODUCTION
Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and safety for ibuprofen and oxycodone were studied.
OBJECTIVE
Primary objectives were to AU2 evaluate if allelic variations would affect clinical effectiveness and adverse events (AEs) occurrence.
METHODS
This pragmatic prospective, observational cohort included children aged 4 to 16 years who were seen in a pediatric emergency department with an acute fracture and prescribed ibuprofen or oxycodone for at-home pain management. Saliva samples were obtained for genotyping of allelic variants, and daily telephone follow-up was conducted for 3 days. Pain was measured using the Faces Pain Scale-Revised.
RESULTS
We included 210 children (n = 140 ibuprofen and n = 70 oxycodone); mean age was 11.1 (±SD 3.5) years, 33.8% were female. Median pain reduction on day 1 was similar between groups [ibuprofen 4 (IQR 2,4) and oxycodone 4 (IQR 2,6), = 0.69]. Over the 3 days, the oxycodone group experienced more AE than the ibuprofen group (78.3% vs 53.2%, < 0.001). Those with a CYP2C9*2 reduced function allele experienced less adverse events with ibuprofen compared with those with a normal functioning allele CYP2C9*1 ( = 0.003). Neither CYP3A4 variants nor CYP2D6 phenotype classification affected clinical effect or AE.
CONCLUSION
Although pain relief was similar, children receiving oxycodone experienced more AE, overall, than those receiving ibuprofen. For children receiving ibuprofen or oxycodone, pain relief was not affected by genetic variations in CYP2C9 or CYP3A4/CYP2D6, respectively. For children receiving ibuprofen, the presence of CYP2C9*2 was associated with less adverse events.
PubMed: 38027465
DOI: 10.1097/PR9.0000000000001113 -
Harm Reduction Journal Oct 2023Due to concerns over potential interactions between some hepatitis C direct-acting antivirals (DAAs) and opioids, we describe adverse event (AE) reports of concomitant...
INTRODUCTION
Due to concerns over potential interactions between some hepatitis C direct-acting antivirals (DAAs) and opioids, we describe adverse event (AE) reports of concomitant use of opioids and DAAs.
METHODS
AEs reported (July 28, 2017-December 31, 2021) with the administration of the DAAs glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir/voxilaprevir, and elbasvir/grazoprevir as suspect products were downloaded from the US Food and Drug Administration AE Reporting System Public Dashboard. The number of AE reports containing opioids (fentanyl, hydrocodone, oxycodone) as co-suspect products/concomitant products were counted and summarized by severity, reporting country and whether an outcome of death was reported. Overdose AEs were counted irrespective of opioid use, and changes over time were assessed.
RESULTS
In total, 40 AEs were reported for DAAs and concomitant fentanyl use, 25 (62.5%) were in the USA, 35 (87.5%) were considered serious, and 14 (35.0%) resulted in death; and 626 were reported with concomitant oxycodone/hydrocodone use, 596 (95.2%) were in the USA, 296 (47.3%) were considered serious, and 28 (4.5%) resulted in death. There were 196 overdose AEs (32 [16%] deaths) declining from 2018 (N = 56) to 2021 (N = 29).
CONCLUSIONS
Treating people with hepatitis C virus (HCV) infection who use drugs is key to achieving HCV elimination. Low numbers of DAA AE reports with opioids may provide reassurance to prioritize HCV treatment in this population. These data contribute to evidence supporting the continued scale-up of DAA treatment among people who use drugs to achieve HCV elimination goals.
Topics: Humans; Sofosbuvir; Antiviral Agents; Hepacivirus; Analgesics, Opioid; Hepatitis C, Chronic; Oxycodone; Hydrocodone; Hepatitis C; Fentanyl
PubMed: 37779203
DOI: 10.1186/s12954-023-00874-y -
The Primary Care Companion For CNS... Nov 2023Opioid misuse/abuse is a pervasive problem in the United States, and the growing use of fentanyl-contaminated products is adding fuel to the opioid crisis. To review... (Review)
Review
Opioid misuse/abuse is a pervasive problem in the United States, and the growing use of fentanyl-contaminated products is adding fuel to the opioid crisis. To review the rising prevalence of nonprescription fentanyl in counterfeit oxycodone, paying specific attention to oxycodone for cost analysis. A literature search was performed using 3 databases (Google Scholar, PubMed, and Clinical Key) to identify English-language articles published from January 2010 to October 2022. Search terms were and . An additional search of was performed to gather more information about the pharmacology behind fentanyl overdoses. Studies and articles were selected based on information related to the presence of non-prescription fentanyl in illicit supplies of oxycodone. Additional articles were included to demonstrate the cost, manufacturing, and overdose rates of fentanyl-laced counterfeit opioids. A total of 13 articles were included in the final review. The demand for illicit oxycodone provides an opportunity in which counterfeiters can thrive, using dangerous adulterating agents such as fentanyl to maximize their profits. Those purchasing oxycodone illicitly may or may not be aware of the presence of fentanyl in their tablets, which has clearly resulted in rising overdose numbers. Clinicians should counsel patients at risk for opioid misuse on the risks of counterfeit oxycodone. .
Topics: Humans; Analgesics, Opioid; Drug Overdose; Fentanyl; Opiate Overdose; Opioid-Related Disorders; Oxycodone; United States
PubMed: 37976226
DOI: 10.4088/PCC.22nr03433 -
BioRxiv : the Preprint Server For... Dec 2023Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the...
Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the development of opioid use disorder. Cannabis and its derivatives such as Δ-Tetrahydrocannabinol (Δ-THC) have been reported to enhance oxycodone analgesia in animal models and in humans. However, it remains unclear if Δ-THC may facilitate unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at analgesic doses. This study sought to evaluate the impact of co-administration of Δ-THC and oxycodone across behavioral measures related to antinociception, dependence, circadian activity, and reward in both male and female mice. Oxycodone and Δ-THC produced dose-dependent antinociceptive effects in the hotplate assay that were similar between sexes. Repeated treatment (twice daily for 5 days) resulted in antinociceptive tolerance. Combination treatment of oxycodone and Δ-THC produced a greater antinociceptive effect than either administered alone, and delayed the development of antinociceptive tolerance. Repeated treatment with oxycodone produced physical dependence and alterations in circadian activity, neither of which were exacerbated by co-treatment with Δ-THC. Combination treatment of oxycodone and Δ-THC produced CPP when co-administered at doses that did not produce preference when administered alone. These data indicate that Δ-THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (e.g. dependence, circadian rhythm alterations). However, our findings also indicate that Δ-THC may facilitate rewarding properties of oxycodone at therapeutically relevant doses which warrant consideration when evaluating this combination for its potential therapeutic utility.
PubMed: 38105953
DOI: 10.1101/2023.12.04.569809 -
BMC Geriatrics Apr 2024Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex...
BACKGROUND
Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA.
METHODS
This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models.
RESULTS
The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons.
CONCLUSIONS
Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.
Topics: Humans; Aged; United States; Analgesics, Opioid; Tramadol; Oxycodone; Arthroplasty, Replacement, Knee; Hydrocodone; Retrospective Studies; Arthroplasty, Replacement, Hip; Medicare
PubMed: 38580920
DOI: 10.1186/s12877-024-04933-2 -
Frontiers in Behavioral Neuroscience 2023The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely...
INTRODUCTION
The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures.
METHODS
In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-h sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests.
RESULTS
In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase.
DISCUSSION
These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.
PubMed: 37465001
DOI: 10.3389/fnbeh.2023.1143373