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The Canadian Veterinary Journal = La... Jun 1998The purpose of this study was to compare the effects of epidural bupivacaine (BUP) and oxymorphone/bupivacaine (O/B) and intravenous (i.v.) oxymorphone (IVO) on... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
End tidal halothane concentration and postoperative analgesia requirements in dogs: a comparison between intravenous oxymorphone and epidural bupivacaine alone and in combination with oxymorphone.
The purpose of this study was to compare the effects of epidural bupivacaine (BUP) and oxymorphone/bupivacaine (O/B) and intravenous (i.v.) oxymorphone (IVO) on halothane requirements during hind end surgery and postoperative analgesia in 24 dogs. Dogs were randomly assigned to treatment groups: O/B--oxymorphone (0.1 mg/kg) in 0.75% bupivacaine (1 mg/kg for a total volume of 0.2 ml/kg); BUP--0.5% bupivacaine (1 mg/kg for a total volume of 0.2 ml/kg) with i.v. oxymorphone (0.05 mg/kg) postoperatively; and IVO--oxymorphone (0.05 mg/kg) pre- and postoperatively. Heart rate (HR), respiratory rate, arterial blood pressure, end-tidal carbon dioxide and halothane, and arterial blood gases were recorded prior to treatment and every 15 minutes thereafter. Once surgery had begun, end-tidal halothane concentrations were decreased as low as possible while still maintaining a stable anesthetic plane. Data were analyzed using ANOVA with P < 0.05 considered significant. End-tidal halothane requirements did not differ significantly among treatments. Respiratory depression was increased and HR was decreased in the O/B and IVO groups. Postoperative analgesic requirements were significantly less in dogs receiving O/B.
Topics: Adjuvants, Anesthesia; Analgesia; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Local; Animals; Blood Gas Analysis; Blood Pressure; Bupivacaine; Carbon Dioxide; Dogs; Female; Halothane; Heart Rate; Injections, Epidural; Injections, Intravenous; Male; Oxymorphone; Pain, Postoperative; Respiration
PubMed: 9635170
DOI: No ID Found -
Anesthesiology Oct 2020The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary... (Review)
Review
The United States Food and Drug Administration is tasked with ensuring the efficacy and safety of medications marketed in the United States. One of their primary responsibilities is to approve the entry of new drugs into the marketplace, based on the drug's perceived benefit-risk relationship. The Anesthetic and Analgesic Drug Product Advisory Committee is composed of experts in anesthesiology, pain management, and biostatistics, as well as consumer and industry representatives, who meet several times annually to review new anesthetic-related drugs, those seeking new indications, and nearly every opioid-related application for approval. The following report describes noteworthy activities of this committee since 2017, as it has grappled, along with the Food and Drug Administration, to balance the benefit-risk relationships for individual patients along with the overarching public health implications of bringing additional opioids to market. All anesthesia advisory committee meetings since 2017 will be described, and six will be highlighted, each with representative considerations for potential new opioid formulations or local anesthetics.
Topics: Advisory Committees; Analgesics; Analgesics, Opioid; Anesthetics; Congresses as Topic; Decision Making; Delayed-Action Preparations; Drug Approval; Humans; Opioid-Related Disorders; Oxymorphone; Spiro Compounds; Thiophenes; United States
PubMed: 32773684
DOI: 10.1097/ALN.0000000000003485 -
Pain Physician Mar 2008For thousands of years, opioids have been used to treat pain, and they continue to be one of the most commonly prescribed medications for pain. It is estimated that 90%... (Review)
Review
For thousands of years, opioids have been used to treat pain, and they continue to be one of the most commonly prescribed medications for pain. It is estimated that 90% of patients presenting to pain centers and receiving treatment in such facilities are on opioids. Opioids can be considered broad-spectrum analgesics that act at multiple points along the pain pathway. Unfortunately, opioids also have the potential for great harm, with multiple side effects and potential complications, some of which are lethal. They are also uniquely addictive, which can lead to misuse and diversion. We reviewed the relevant English literature and did thorough manual searches of the bibliographies of known primary and review articles. We utilized pain relief as the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, improvement in work status, and evidence of addiction. Short-term use and improvement was defined as less than 6 months and long-term relief was defined as 6 months or longer. The 3 systematic reviews evaluating long-term effectiveness of opioids for chronic non-cancer pain provided unclear and weak evidence. The results of this review showed that many patients in the included studies were dissatisfied with adverse events or insufficient pain relief from opioids and withdrew from the studies. For patients able to continue on opioids, evidence was weak suggesting that their pain scores were lower than before therapy and that this relief could be maintained long-term (> 6 months). There was also weak evidence that long-term opioid therapy with morphine and transdermal fentanyl not only decreases pain but also improves functioning. Limited evidence was available for the most commonly used opioids, oxycodone and hydrocodone. Evidence for the ability to drive on chronic opioid therapy was moderate without major side effects or complications. It is concluded that, for long-term opioid therapy of 6 months or longer in managing chronic non-cancer pain, with improvement in function and reduction in pain, there is weak evidence for morphine and transdermal fentanyl. However, there is limited or lack of evidence for all other controlled substances, including the most commonly used drugs, oxycodone and hydrocodone.
Topics: Analgesics, Opioid; Drug Administration Schedule; Fentanyl; Humans; Methadone; Morphine; Oxycodone; Oxymorphone; Pain; Quality of Life; Time Factors; Tramadol
PubMed: 18443639
DOI: No ID Found -
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 -
Journal of Palliative Medicine Nov 2022Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To...
Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To propose a summary of current opioid equianalgesic data that include variations and trends among national institutions. Opioid equianalgesic tools were obtained between May and September 2021. For meperidine, tramadol, codeine, hydrocodone, morphine, oxycodone, oxymorphone, hydromorphone, levorphanol, fentanyl, and tapentadol, details of adjustment for incomplete tolerance, opioid equianalgesic ratios, and formulation types were collected and analyzed. Baseline opioid pharmaco kinetic data were obtained through manufacturer labels on FDA databases, including half-life (), volume of distribution (), clearance (Cl), area under the curve (AUC), max concentration (), and time to max concentration (). Thirty-two institutions' equianalgesic tools were included with each study opioid appearing on an average of 23 institutions' tools. Few tools contained guidance on levorphanol or tapentadol; or included minimum and maximum recommended doses. All tools included guidance on fentanyl, hydromorphone, oxycodone, morphine, and hydrocodone. A minority of tools included guidance on cross-tolerance considerations ( = 12, 37.5%). Oral-tramadol-to-oral-morphine and oral-hydromorphone-to-intravenous (IV)-hydromorphone had the largest variances across equianalgesic tools (6.7 ± 2.8 and 4.06 ± 1.2 mg, respectively). Opioid equianalgesia tools from across the United States demonstrated significant variation in their inclusion of guidance on adjustment for incomplete cross-tolerance, oral-to-IV, and oral-to-oral opioid equianalgesic ratios, and which opioids and formulations were listed. Tramadol and hydromorphone had the most variation in their equianalgesic guidance among the opioids.
Topics: Humans; Analgesics, Opioid; Hydromorphone; Oxycodone; Tapentadol; Tramadol; Levorphanol; Hydrocodone; Administration, Oral; Fentanyl; Morphine
PubMed: 35559657
DOI: 10.1089/jpm.2021.0678 -
British Journal of Anaesthesia Jul 2009Opioid receptors are currently classified as mu (mu: mOP), delta (delta: dOP), kappa (kappa: kOP) with a fourth related non-classical opioid receptor for... (Review)
Review
Opioid receptors are currently classified as mu (mu: mOP), delta (delta: dOP), kappa (kappa: kOP) with a fourth related non-classical opioid receptor for nociceptin/orphainin FQ, NOP. Morphine is the current gold standard analgesic acting at MOP receptors but produces a range of variably troublesome side-effects, in particular tolerance. There is now good laboratory evidence to suggest that blocking DOP while activating MOP produces analgesia (or antinociception) without the development of tolerance. Simultaneous targeting of MOP and DOP can be accomplished by: (i) co-administering two selective drugs, (ii) administering one non-selective drug, or (iii) designing a single drug that specifically targets both receptors; a bivalent ligand. Bivalent ligands generally contain two active centres or pharmacophores that are variably separated by a chemical spacer and there are several interesting examples in the literature. For example linking the MOP agonist oxymorphone to the DOP antagonist naltrindole produces a MOP/DOP bivalent ligand that should produce analgesia with reduced tolerance. The type of response/selectivity produced depends on the pharmacophore combination (e.g. oxymorphone and naltrindole as above) and the space between them. Production and evaluation of bivalent ligands is an emerging field in drug design and for anaesthesia, analgesics that are designed not to be highly selective morphine-like (MOP) ligands represents a new avenue for the production of useful drugs for chronic (and in particular cancer) pain.
Topics: Analgesia; Analgesics, Opioid; Drug Therapy, Combination; Drug Tolerance; Humans; Ligands; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu
PubMed: 19474215
DOI: 10.1093/bja/aep129 -
Pharmacogenomics Mar 2017Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects... (Observational Study)
Observational Study
AIM
Oxycodone is partly metabolized to the active metabolite oxymorphone by hepatic CYP2D6 in the liver. Significant genetic variability in CYP2D6 activity affects oxymorphone formation. This study aimed to associate CYP2D6 genotype and oxycodone's metabolism.
METHODS
30 children were administered oral oxycodone postoperatively. Plasma levels of oxycodone and oxymorphone, and CYP2D6 genotype were analyzed. CYP2D6 genotype and oxycodone metabolism phenotype were determined based on CYP2D6 total activity score (TAS) and metabolism phenotype: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM) or ultrarapid metabolizer (UM).
RESULTS
Compared with PM/IM subjects, significantly greater oxymorphone exposure was seen in EM subjects (p = 0.02 for C, p = 0.016 for AUC and p = 0.026 for AUC). Similarly, higher TAS value was found to be associated with greater oxymorphone exposure. Higher conversion of oxycodone to oxymorphone was observed in EM subjects compared with PM/IM subjects (p = 0.0007 for C, p = 0.001 for AUC and p = 0.004 for AUC).
CONCLUSION
CYP2D6 phenotypes explain metabolism of oxycodone in children, and oxymorphone exposure is higher in CYP2D6 EM phenotype. Further studies are needed to predict the occurrence of adverse event and tailor oxycodone dose for a specific CYP2D6 phenotype.
Topics: Administration, Oral; Adolescent; Analgesics, Opioid; Child; Child, Preschool; Cytochrome P-450 CYP2D6; Female; Humans; Male; Oxycodone; Pain, Postoperative; Pharmacogenetics; Pilot Projects; Prospective Studies
PubMed: 28244808
DOI: 10.2217/pgs-2016-0183 -
Pharmacogenomics and Personalized... 2012Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the...
Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.
PubMed: 23226064
DOI: 10.2147/PGPM.S23422 -
Frontiers in Pharmacology 2023The United States (US) ranks high, nationally, in opioid consumption. The ongoing increase in the misuse and mortality amid the opioid epidemic has been contributing to...
The United States (US) ranks high, nationally, in opioid consumption. The ongoing increase in the misuse and mortality amid the opioid epidemic has been contributing to its rising cost. The worsening health and economic impact of opioid use disorder in the US warrants further attention. We, therefore, assessed commonly prescribed opioids to determine the opioids that were over-represented versus under-represented for adverse drug events (ADEs) to better understand their distribution patterns using the Food and Drug Administration's Adverse Event Reporting System (FAERS) while correcting for distribution using the Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS). Comparing the ratio of the percentage of adverse drug events as reported by the FAERS relative to the percentage of distribution as reported by the ARCOS database is a novel approach to evaluate post-marketing safety surveillance and may inform healthcare policies and providers to better regulate the use of these opioids. We analyzed the adverse events for 11 prescription opioids, when correcting for distribution, and their ratios for three periods, 2006-2010, 2011-2016, and 2017-2021, in the US. The opioids include buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Oral morphine milligram equivalents (MMEs) were calculated by conversions relative to morphine. The relative ADEs of the selected opioids, opioid distributions, and ADEs relative to distribution ratios were analyzed for the 11 opioids. Oxycodone, fentanyl, and morphine accounted for over half of the total number of ADEs ( = 667,969), while meperidine accounted for less than 1%. Opioid distributions were relatively constant over time, with methadone repeatedly accounting for the largest proportions. Many ADE-to-opioid distribution ratios increased over time, with meperidine (60.6), oxymorphone (11.1), tapentadol (10.3), and hydromorphone (7.9) being the most over-represented for ADEs in the most recent period. Methadone was under-represented (<0.20) in all the three periods. The use of the FAERS with the ARCOS provides insights into dynamic changes in ADEs of the selected opioids in the US. There is further need to monitor and address the ADEs of these drugs.
PubMed: 37033633
DOI: 10.3389/fphar.2023.1163976 -
JMIR Public Health and Surveillance Jun 2020Between 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health...
BACKGROUND
Between 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health crisis to a new height. Considering that 69% of adults in the United States use online social media sites, a resource that builds a more complete understanding of prescription drug misuse and abuse could supplement traditional surveillance instruments. The Food and Drug Administration has identified 5 key risks and consequences of opioid drugs-misuse, abuse, addiction, overdose, and death. Identifying posts that discuss these key risks could lead to novel information that is not typically captured by traditional surveillance systems.
OBJECTIVE
The goal of this study was to describe the trends of online posts (frequency over time) involving abuse, misuse, addiction, overdose, and death in the United States and to describe the types of websites that host these discussions. Internet posts that mentioned fentanyl, hydrocodone, oxycodone, or oxymorphone were examined.
METHODS
Posts that did not refer to personal experiences were removed, after which 3.1 million posts remained. A stratified sample of 61,000 was selected. Unstructured data were classified into 5 key risks by manually coding for key outcomes of misuse, abuse, addiction, overdose, and death. Sampling probabilities of the coded posts were used to estimate the total post volume for each key risk.
RESULTS
Addiction and misuse were the two most commonly discussed key risks for hydrocodone, oxycodone, and oxymorphone. For fentanyl, overdose and death were the most discussed key risks. Fentanyl had the highest estimated number of misuse-, overdose-, and death-related mentions (41,808, 42,659, and 94,169, respectively). Oxycodone had the highest estimated number of abuse- and addiction-related mentions (3548 and 12,679, respectively). The estimated volume of online posts for fentanyl increased by more than 10-fold in late 2017 and 2018. The odds of discussing fentanyl overdose (odds ratios [OR] 4.32, 95% CI 2.43-7.66) and death (OR 5.05, 95% CI 3.10-8.21) were higher for social media, while the odds of discussing fentanyl abuse (OR 0.10, 95% CI 0.04-0.22) and addiction (OR 0.24, 95% CI 0.15-0.38) were higher for blogs and forums.
CONCLUSIONS
Of the 5 FDA-defined key risks, fentanyl overdose and death has dominated discussion in recent years, while discussion of oxycodone, hydrocodone, and oxymorphone has decreased. As drug-related deaths continue to increase, an understanding of the motivations, circumstances, and consequences of drug abuse would assist in developing policy responses. Furthermore, content was notably different based on media origin, and studies that exclusively use either social media sites (such as Twitter) or blogs and forums could miss important content. This study sets out sustainable, ongoing methodology for surveilling internet postings regarding these drugs.
Topics: Adult; Analgesics, Opioid; Epidemiology; Female; Fentanyl; Humans; Hydrocodone; Male; Middle Aged; Odds Ratio; Opioid Epidemic; Oxycodone; Oxymorphone; Population Surveillance; Social Media; Substance-Related Disorders; United States
PubMed: 32597786
DOI: 10.2196/17073