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European Journal of Pharmaceutical... Mar 2024Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the...
Exploring the impact of CYP2D6 and UGT2B7 gene-drug interactions, and CYP-mediated DDI on oxycodone and oxymorphone pharmacokinetics using physiologically-based pharmacokinetic modeling and simulation.
Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.
Topics: Humans; Oxycodone; Oxymorphone; Cytochrome P-450 CYP2D6; Ketoconazole; Cytochrome P-450 CYP3A; Drug Interactions; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 CYP3A Inducers; Guanine Nucleotide Dissociation Inhibitors; Glucuronosyltransferase
PubMed: 38171419
DOI: 10.1016/j.ejps.2023.106689 -
Experimental Biology and Medicine... Nov 2023The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the...
The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the risks presented by opioid exposure, as well as the individual risk profiles of specific opioid drugs and the potential relationships among the opioids. In this study, 92 opioids were identified from the list of all Food and Drug Administration (FDA)-approved drugs, annotated by RxNorm and were classified into 13 opioid groups: buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol. A total of 14,970,399 AE reports were retrieved and downloaded from the FDA Adverse Events Reporting System (FAERS) from 2004, Quarter 1 to 2020, Quarter 3. After data processing, Empirical Bayes Geometric Mean (EBGM) was then applied which identified 3317 pairs of potential risk signals within the 13 opioid groups. Based on these potential safety signals, a comparative analysis was pursued to provide a global overview of opioid-related AEs for all 13 groups of FDA-approved prescription opioids. The top 10 most reported AEs for each opioid class were then presented. Both network analysis and hierarchical clustering analysis were conducted to further explore the relationship between opioids. Results from the network analysis revealed a close association among fentanyl, oxycodone, hydrocodone, and hydromorphone, which shared more than 22 AEs. In addition, much less commonly reported AEs were shared among dihydrocodeine, meperidine, oxymorphone, and tapentadol. On the contrary, the hierarchical clustering analysis further categorized the 13 opioid classes into two groups by comparing the full profiles of presence/absence of AEs. The results of network analysis and hierarchical clustering analysis were not only consistent and cross-validated each other but also provided a better and deeper understanding of the associations and relationships between the 13 opioid groups with respect to their adverse effect profiles.
Topics: Analgesics, Opioid; Bayes Theorem; Data Mining; Fentanyl; Hydrocodone; Hydromorphone; Meperidine; Oxycodone; Oxymorphone; Tapentadol; United States
PubMed: 38158803
DOI: 10.1177/15353702231211860 -
Cureus Nov 2023Objective The aim of this study was to describe various aspects related to opioid use and storage in the setting of at-home pain management after cesarean deliveries...
Objective The aim of this study was to describe various aspects related to opioid use and storage in the setting of at-home pain management after cesarean deliveries among an Appalachian population. Methods Women who underwent cesarean delivery (January-June 2019) at an Appalachian institution were prospectively enrolled and administered a telephone survey seven (± 3) days post-discharge. Results Of the 87 women enrolled, 40 (46%) completed the survey; 92.5% were prescribed an opioid medication, most commonly oxycodone/acetaminophen 5/325 mg. A Kruskal-Wallis H test revealed a significant association between the severity of pain that interfered with normal daily activities and the number of pills consumed [χ2(2)=6.75, p=0.034]. More than 70% of the participants (28/40) had not safely stored or disposed of their unused opioid medications. Conclusion Our findings highlight the need for interventions to educate patients on how to appropriately use, store, and dispose of unused opioids.
PubMed: 38152813
DOI: 10.7759/cureus.49474 -
Frontiers in Psychiatry 2023The over-prescription of opioid analgesics is a growing problem in the field of addiction, which has reached epidemic-like proportions in North America. Over the past... (Review)
Review
The over-prescription of opioid analgesics is a growing problem in the field of addiction, which has reached epidemic-like proportions in North America. Over the past decade, oxycodone has gained attention as the leading opioid responsible for the North America opioid crisis. Oxycodone is the most incriminated drug in the early years of the epidemic of opioid use disorder in USA (roughly 1999-2016). The number of preclinical articles on oxycodone is rapidly increasing. Several publications have already compared oxycodone with other opioids, focusing mainly on their analgesic properties. The aim of this review is to focus on the genomic and epigenetic regulatory features of oxycodone compared with other opioid agonists. Our aim is to initiate a discussion of perceptible differences in the pharmacological response observed with these various opioids, particularly after repeated administration in preclinical models commonly used to study drug dependence potential.
PubMed: 38152360
DOI: 10.3389/fpsyt.2023.1229439 -
BJS Open Nov 2023While opioid analgesics are often necessary for the management of acute postoperative pain, appropriate prescribing practices are crucial to avoid harm. The aim was to...
BACKGROUND
While opioid analgesics are often necessary for the management of acute postoperative pain, appropriate prescribing practices are crucial to avoid harm. The aim was to investigate the changes in the proportion of people receiving initial opioid prescriptions after hospital discharge following colectomy, and describe trends and patterns in prescription characteristics.
METHODS
This was a retrospective cohort study. Patients undergoing colectomy in England between 2010 and 2019 were included using electronic health record data from linked primary (Clinical Practice Research Datalink Aurum) and secondary (Hospital Episode Statistics) care. The proportion of patients having an initial opioid prescription issued in primary care within 90 days of hospital discharge was calculated. Prescription characteristics of opioid type and formulation were described.
RESULTS
Of 95 155 individuals undergoing colectomy, 15 503 (16.3%) received opioid prescriptions. There was a downward trend in the proportion of patients with no prior opioid exposure (opioid naive) who had a postdischarge opioid prescription (P <0.001), from 11.4% in 2010 to 6.7% in 2019 (-41.3%, P <0.001), whereas the proportions remained stable for those prescribed opioids prior to surgery, from 57.5% in 2010 to 58.3% in 2019 (P = 0.637). Codeine represented 44.5% of all prescriptions and prescribing increased by 14.5% between 2010 and 2019. Prescriptions for morphine and oxycodone rose significantly by 76.6% and 31.0% respectively, while tramadol prescribing dropped by 48.0%. The most commonly prescribed opioid formulations were immediate release (83.9%), followed by modified release (5.8%) and transdermal (3.2%). There was a modest decrease in the prescribing of immediate-release formulations from 86.0% in 2010 to 82.0% in 2019 (P <0.001).
CONCLUSION
Over the 10 years studied, there was a changing pattern of opioid prescribing following colectomy, with a decrease in the proportion of opioid-naive patients prescribed postdischarge opioids.
Topics: Humans; Analgesics, Opioid; Retrospective Studies; Patient Discharge; Aftercare; Practice Patterns, Physicians'; England; Prescriptions; Colectomy
PubMed: 38146708
DOI: 10.1093/bjsopen/zrad136 -
World Journal of Plastic Surgery 2023We aimed to investigate the pharmacological and non-pharmacological interventions used for mitigating pain. (Review)
Review
BACKGROUND
We aimed to investigate the pharmacological and non-pharmacological interventions used for mitigating pain.
METHODS
We integrated randomized controlled trials (RCTs) chosen from PubMed, Google scholar, and Scopus and aimed at assessing the effectiveness of one or multiple variants of Non-steroidal anti-inflammatory drugs (NSAIDs), as well as Narcotic analgesics, compared to corticosteroids, curcumin, hyaluronic acid, and antibiotics. In addition, trials utilizing NSAIDs, including Rofecoxib, which have been withdrawn from market circulation, were deemed ineligible for inclusion.
RESULT
A total of 9 RCTs were evaluated in this study, and the patients' postoperative pain was assessed using the visual analog scale (VAS) and the time measurement. Moreover, there were various approaches to alleviating pain and discomfort.
CONCLUSION
The administration of ibuprofen prior to surgery leads to a marked reduction in pain. Pharmacological interventions, such as the administration of dexamethasone and oxycodone, alongside non-pharmacological interventions, such as laser therapy, have been shown to effectively alleviate the discomfort resulting from surgical procedures on the jaw and face.
PubMed: 38130382
DOI: 10.52547/wjps.12.2.3 -
Scandinavian Journal of Pain Jan 2024A pneumatic tourniquet is often used during ankle fracture surgery to reduce bleeding and enhance the visibility of the surgical field. Tourniquet use causes both...
OBJECTIVES
A pneumatic tourniquet is often used during ankle fracture surgery to reduce bleeding and enhance the visibility of the surgical field. Tourniquet use causes both mechanical and ischemic pain. The main purpose of this study was to evaluate the effect of tourniquet time on postoperative opioid consumption after ankle fracture surgery.
METHODS
We retrospectively reviewed the files of 586 adult patients with surgically treated ankle fractures during the years 2014-2016. We evaluated post hoc the effect of tourniquet time on postoperative opioid consumption during the first 24 h after surgery. The patients were divided into quartiles by the tourniquet time (4-43 min; 44-58 min; 59-82 min; and ≥83 min). Multivariable linear regression analysis was used to evaluate the results.
RESULTS
Tourniquets were used in 486 patients. The use of a tourniquet was associated with an increase in the total postoperative opioid consumption by 5.1 mg (95 % CI 1.6-8.5; p=0.004) during the first 24 postoperative hours. The tourniquet time over 83 min was associated with an increase in the mean postoperative oxycodone consumption by 5.4 mg (95 % CI 1.2 to 9.7; p=0.012) compared to patients with tourniquet time of 4-43 min.
CONCLUSIONS
The use of a tourniquet and prolonged tourniquet time were associated with higher postoperative opioid consumption during the 24 h postoperative follow-up after surgical ankle fracture fixation. The need for ethical approval and informed consent was waived by the Institutional Review Board of Northern Ostrobothnia Health District because of the retrospective nature of the study.
Topics: Adult; Humans; Ankle Fractures; Retrospective Studies; Analgesics, Opioid; Tourniquets; Pain, Postoperative
PubMed: 38126186
DOI: 10.1515/sjpain-2023-0051 -
International Journal of Clinical... 2023Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an invasive procedure that required deep sedation to suppress coughing and body... (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Combined with Propofol TCI versus Propofol TCI for Deep Sedation during Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: A Prospective, Randomized, and Controlled Trial.
BACKGROUND
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an invasive procedure that required deep sedation to suppress coughing and body movements. Deep sedation, on the other hand, has been shown to cause respiratory and circulatory depression, especially when the airway is shared with the endoscopist. Esketamine is a novel sedative and analgesic with little respiratory inhibition that appears to be an appropriate adjuvant in propofol sedation for EBUS-TBNA. We compared the efficacy and safety of esketamine combined with propofol target-controlled infusion (TCI) and propofol TCI for deep sedation in EBUS-TBNA.
METHODS
The study included 135 patients with ASA II-III undergoing EBUS-TBNA. They were randomly divided into two groups (group E and group P). Both groups received midazolam (0.01-0.03 mg/kg) and oxycodone (0.07-0.08 mg/kg). Then, patients in group E received 0.3 mg/kg esketamine, propofol TCI, and 0.2 mg·kg·h esketamine for sedative maintenance. Patients in group P received only propofol TCI. The primary outcome was the dose of 1% lidocaine administrated by the endoscopist and the times of lidocaine sprays. Secondary outcome indicators were cough score, propofol dosage, patient satisfaction, endoscopist satisfaction, the incidence of sedation-related adverse effects and side effects, and recovery time.
RESULTS
Patients in group E were given significantly less lidocaine (4.36 ml/h (2.67-6.00) vs 6.00 ml/h (4.36-7.20), < 0.001) and less spraying frequency (2.18 times/h (1.33-3.00) vs 3.00 times/h (2.18-3.60), < 0.001) than group P. There was a statistically significant difference in cough score between the two groups (group E 2 (0-4) vs group P 3 (2-4), =0.03). Also, mean arterial pressure (MAP) was higher in group E in the 30 min (T5, 84.10 ± 12.91 mmHg versus 79.04 ± 10.01 mmHg, =0.012) and 40 min (T6, 87.72 ± 15.55 mmHg versus 82.14 ± 10.51 mmHg, =0.026). There were no significant differences between the two groups in terms of sedation-related adverse events and side effects, recovery time, endoscopist satisfaction, and patient satisfaction.
CONCLUSIONS
In patients with ASA II-III, esketamine as an adjuvant in combination with propofol TCI deep sedation for EBUS-TBNA can improve the sedation effect, reduce coughing reaction during the procedure, and obtain more stable blood pressure. No reduction in the occurrence of sedation-related side effects was observed. This trial is registered with ChiCTR2200061124.
Topics: Humans; Propofol; Prospective Studies; Deep Sedation; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Hypnotics and Sedatives; Cough; Lidocaine
PubMed: 38115950
DOI: 10.1155/2023/1155126 -
Pain Jun 2024Current research indicates that tapering opioids may improve pain and function in patients with chronic noncancer pain. However, gaps in the literature remain regarding...
Current research indicates that tapering opioids may improve pain and function in patients with chronic noncancer pain. However, gaps in the literature remain regarding the choice of opioid and nonopioid interventions to support a successful taper. This study used an Australian primary care data set to identify a cohort of patients on long-term opioid therapy commencing opioid taper between January 2016 and September 2019. Using logistic regression analysis, we compared key clinical factors associated with differing taper outcomes. Of a total of 3371 patients who commenced taper, 1068 (31.7%) completed taper within 12 months. In the 3 months after commencement of taper, compared with those who did not complete taper, patients who successfully completed opioid taper were less likely to be prescribed buprenorphine (odds ratio [OR] 0.691; 95% CI: 0.530-0.901), fentanyl (OR, 0.429; 95% CI: 0.295-0.622), and long-acting (LA) opioids, including methadone (OR, 0.349; 95% CI: 0.157-0.774), oxycodone-naloxone (OR, 0.521; 95% CI: 0.407-0.669), and LA tapentadol (OR, 0.645; 95% CI: 0.461-0.902), but more likely to be prescribed codeine (OR, 1.308; 95% CI: 1.036-1.652). Compared with those who did not complete taper, patients who successfully tapered were less likely to be prescribed any formulations of oxycodone (short-acting [SA]: OR, 0.533; 95% CI: 0.422-0.672, LA: OR, 0.356; 95% CI: 0.240-0.530) and tramadol (SA: OR, 0.370; 95% CI: 0.218-0.628, LA: OR, 0.317; 95% CI: 0.234-0.428). The type of opioid prescribed in the months after commencement of taper seems to influence the taper outcomes. These findings may inform prospective studies on opioid taper.
Topics: Humans; Chronic Pain; Male; Female; Analgesics, Opioid; Middle Aged; Aged; Adult; Australia; Cohort Studies
PubMed: 38112755
DOI: 10.1097/j.pain.0000000000003133 -
British Journal of Pain Oct 2023The prescription of opioids in emergency care has been associated with harm, including overdose and dependence. The aim of this trial was to assess restriction of access...
BACKGROUND
The prescription of opioids in emergency care has been associated with harm, including overdose and dependence. The aim of this trial was to assess restriction of access to oxycodone (ROXY), in combination with education and guideline modifications, versus education and guideline modifications alone (standard care) to reduce oxycodone administration in the Emergency Department (ED).
METHODS
An unblinded, active control, randomised controlled trial was conducted in an adult tertiary ED. Participants were patients aged 18-75 years who had analgesics administered in the ED. The primary intervention was ROXY, through removal of all oxycodone immediate release tablets from the ED imprest, with availability of a small supply after senior clinician approval. The intervention did not restrict prescription of discharge medications. The primary outcome measure was oxycodone administration rates. Secondary outcomes were administration rates of other analgesic medications, time to initial analgesics and oxycodone prescription on discharge.
RESULTS
There were 2258 patients eligible for analysis. Oxycodone was administered to 80 (6.1%) patients in the ROXY group and 221 (23.3%) patients in the standard care group (relative risk (RR) 0.26; 95% CI: 0.21 to 0.33; < .001). Tapentadol was prescribed more frequently in the ROXY group (RR 2.17; 95% CI: 1.71-2.74), while there were no differences in prescription of other analgesic medications. On discharge, significantly fewer patients were prescribed oxycodone (RR 0.51; 95% CI: 0.39-0.66) and no differences were observed in prescription rates of other analgesic medications. There was no difference in time to first analgesic (HR 0.94; 95% CI: 0.86-1.02).
CONCLUSIONS
Restricted access to oxycodone was superior to education and guideline modifications alone for reducing oxycodone use in the ED and reducing discharge prescriptions of oxycodone from the ED. The addition of simple restrictive interventions is recommended to enable rapid changes to clinician behaviour to reduce the potential harm associated with the prescribing of oxycodone in the ED.
PubMed: 38107754
DOI: 10.1177/20494637231189031