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Forensic Science International. Genetics Jul 2021Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine,...
Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.
Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Cytochrome P-450 CYP2D6; DNA Copy Number Variations; Female; Forensic Genetics; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Morphinans; Oxycodone; Pharmacogenomic Testing; Phenotype; Polymorphism, Single Nucleotide; Young Adult
PubMed: 33799050
DOI: 10.1016/j.fsigen.2021.102510 -
British Journal of Clinical Pharmacology Dec 2022The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials.
METHODS
Twenty-one healthy volunteers completed a cross-over trial with oxycodone (10 mg), tapentadol (50 mg) extended-release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post-interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory-evoked potential.
RESULTS
Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by -0.89 (P = .001, 95% confidence interval [CI] -1.46, -0.32), whereas oxycodone increased the latency of the N1 component of the sensory-evoked potential at the vertex by 12.5 ms (P = .003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P < .02), and the insula components moved caudally in both the oxycodone and tapentadol arms (all P < .03).
CONCLUSION
A decrease in the number of nociceptive withdrawal reflex was observed during tapentadol treatment, possibly relating to the noradrenaline reuptake inhibition effects on the spinal cord. Both oxycodone and tapentadol affected cortical measures possible due to μ-opioid receptor agonistic effects evident in the dipole sources, with the strongest effect being mediated by oxycodone. These findings could support the dual effect analgesic mechanisms of tapentadol in humans as previously shown in preclinical studies.
Topics: Humans; Tapentadol; Oxycodone; Phenols; Analgesics, Opioid; Spinal Cord; Brain; Electrophysiology; Double-Blind Method
PubMed: 35776835
DOI: 10.1111/bcp.15453 -
British Journal of Clinical Pharmacology Mar 2022Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas... (Randomized Controlled Trial)
Randomized Controlled Trial
Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas tapentadol also affects noradrenergic activity. However, knowledge about the function of the medications in the human brain is limited. The aim was to investigate effects of tapentadol and oxycodone on brain glutamate, the most important neurotransmitter in pain processing. Magnetic resonance spectroscopy was obtained in 21 healthy subjects from the anterior cingulate cortex, prefrontal cortex, and insula at baseline and after 14 days of treatment with either 50 mg tapentadol, 10 mg oxycodone (equipotent dose, both extended release) or placebo twice daily in a randomized double-blind cross-over study. Compared to baseline, decreased glutamate/creatine levels were identified in anterior cingulate cortex after tapentadol (1.26 ± 0.14 vs. 1.35 ± 0.18, P = .04) and oxycodone (1.26 ± 0.10 vs. 1.35 ± 0.12, P = .05) treatments, both with 7% reduction. This indicates that both analgesics modulate the glutamatergic system at the supraspinal level in humans.
Topics: Analgesics; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Glutamic Acid; Healthy Volunteers; Humans; Oxycodone; Phenols; Tapentadol
PubMed: 34427941
DOI: 10.1111/bcp.15050 -
British Journal of Clinical Pharmacology Oct 2017Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review... (Meta-Analysis)
Meta-Analysis Review
AIMS
Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant.
METHODS
We systematically reviewed the literature to September 11, 2016, to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale.
RESULTS
A total of 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified, as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and warfarin.
CONCLUSIONS
The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.
Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Ethanol; Humans; Injection Site Reaction; Morpholines; Nausea; Oxycodone; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Vomiting
PubMed: 28470980
DOI: 10.1111/bcp.13322 -
Pain Physician Feb 2017Opioids are the mainstay of pain management for acute postsurgical pain. Oral oxycodone is an opioid that can provide effective acute postoperative pain relief. (Review)
Review
BACKGROUND
Opioids are the mainstay of pain management for acute postsurgical pain. Oral oxycodone is an opioid that can provide effective acute postoperative pain relief.
OBJECTIVES
To evaluate the use of oral oxycodone for acute postoperative pain management.
STUDY DESIGN
This is a narrative review based on published articles searched in PubMed and Medline from 2003 to 2015 on oral oxycodone for acute postoperative pain management.
METHODS
Clinical trials related to the use of oral oxycodone for acute postoperative pain management were searched via PubMed and Medline from 2003 to 2015. The search terms used were "oral strong opioids," "postsurgical," "postoperative," "post-surgical," and "post-operative." Treatment interventions were compared for analgesic efficacy, rescue medication use, side effects, recovery, length of hospital stay, and patient satisfaction.
RESULTS
There were 26 clinical trials included in the review. Oral oxycodone showed superior postoperative analgesic efficacy compared with placebo in patients undergoing laparoscopic cholecystectomy, abdominal or pelvic surgery, bunionectomy, breast surgery, and spine surgery. When compared with intravenous opioids, oral oxycodone provided better or comparable pain relief following knee arthroplasty, spine surgery, caesarean section, laparoscopic colorectal surgery, and cardiac surgery. One study of dental postsurgery pain reported inferior pain control with oral oxycodone versus rofecoxib. (withdrawn from the US market due to cardiac safety concerns). In many studies, the demand for rescue analgesia and total opioid consumption were reduced in the oxycodone treatment arm. Patients receiving oral oxycodone experienced fewer opioid-related side effects than those on other opioids, and had a similar occurrence of postoperative nausea and vomiting as patients on placebo. Furthermore, oral oxycodone did not prolong hospital stay and was associated with lower drug costs compared with epidural and intravenous analgesics. Oxycodone administered as part of a multimodal analgesic regimen produced superior pain relief with fewer side effects and a reduced hospital stay.
LIMITATIONS
There is a limited number of randomized double blinded studies in individual surgical operations, thus making it more difficult to come up with definitive conclusions.
CONCLUSION
Oral oxycodone appears to offer safe and effective postoperative analgesia, and is a well-accepted and reasonable alternative to standard intravenous opioid analgesics.Key words: Postoperative, pain, analgesia, oral oxycodone, opioid.
Topics: Analgesia; Analgesics, Opioid; Clinical Trials as Topic; Female; Humans; Oxycodone; Pain Measurement; Pain, Postoperative; Pregnancy
PubMed: 28226340
DOI: No ID Found -
Pharmacology, Biochemistry, and Behavior Dec 2021Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This...
BACKGROUND
Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting.
METHODS
After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured.
RESULTS
One hundred twenty-eight adults (age 35-85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects.
CONCLUSION
Independent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alcohol Drinking; Analgesics, Opioid; Attention; Automobile Driving; Cognition; Ethanol; Female; Humans; Male; Memory, Short-Term; Middle Aged; Miosis; Oxycodone; Pain; Sex Factors; Surveys and Questionnaires
PubMed: 34742948
DOI: 10.1016/j.pbb.2021.173295 -
Neuropsychopharmacology : Official... Jun 2017Regulator of G-protein signaling 9-2 (RGS9-2) is a striatal-enriched signal-transduction modulator known to have a critical role in the development of addiction-related...
Regulator of G-protein signaling 9-2 (RGS9-2) is a striatal-enriched signal-transduction modulator known to have a critical role in the development of addiction-related behaviors following exposure to psychostimulants or opioids. RGS9-2 controls the function of several G-protein-coupled receptors, including dopamine receptor and mu opioid receptor (MOR). We previously showed that RGS9-2 complexes negatively control morphine analgesia, and promote the development of morphine tolerance. In contrast, RGS9-2 positively modulates the actions of other opioid analgesics, such as fentanyl and methadone. Here we investigate the role of RGS9-2 in regulating responses to oxycodone, an MOR agonist prescribed for the treatment of severe pain conditions that has addictive properties. Using mice lacking the Rgs9 gene (RGS9KO), we demonstrate that RGS9-2 positively regulates the rewarding effects of oxycodone in pain-free states, and in a model of neuropathic pain. Furthermore, although RGS9-2 does not affect the analgesic efficacy of oxycodone or the expression of physical withdrawal, it opposes the development of oxycodone tolerance, in both acute pain and chronic neuropathic pain models. Taken together, these data provide new information on the signal-transduction mechanisms that modulate the rewarding and analgesic actions of oxycodone.
Topics: Analgesics, Opioid; Animals; Chronic Pain; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxycodone; Pain Measurement; RGS Proteins; Treatment Outcome
PubMed: 28074831
DOI: 10.1038/npp.2017.4 -
The Cochrane Database of Systematic... Jul 2009Oxycodone is a strong opioid agonist used to treat severe pain. It is commonly combined with milder analgesics such as paracetamol. This review updates a previous review... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Oxycodone is a strong opioid agonist used to treat severe pain. It is commonly combined with milder analgesics such as paracetamol. This review updates a previous review that concluded, based on limited data, that all doses of oxycodone exceeding 5 mg, with or without paracetamol, provided analgesia in postoperative pain, but with increased incidence of adverse events compared with placebo. Additional new studies provide more reliable estimates of efficacy and harm.
OBJECTIVES
To assess efficacy, duration of action, and associated adverse events of single dose oral oxycodone, with or without paracetamol, in acute postoperative pain in adults.
SEARCH STRATEGY
Cochrane CENTRAL, MEDLINE, EMBASE and Oxford Pain Relief Database, searched in May 2009.
SELECTION CRITERIA
Randomised, double blind, placebo-controlled trials of single dose orally administered oxycodone, with or without paracetamol, in adults with moderate to severe acute postoperative pain.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants remedicating over specified time periods, and time-to-use of rescue medication, were sought as additional measures of efficacy. Adverse events and withdrawals information was collected.
MAIN RESULTS
This updated review includes 20 studies, with 2641 participants. For oxycodone 15 mg alone compared with placebo, the NNT for at least 50% pain relief was 4.6 (95% Confidence Interval 2.9 to 11). For oxycodone 10 mg plus paracetamol 650 mg, the NNT was 2.7 (2.4 to 3.1). A dose response was demonstrated for this outcome with combination therapy. Duration of effect was 10 hours with oxycodone 10 mg plus paracetamol 650 mg, and 4 hours with half that dose. Fewer participants needed rescue medication over 6 hours at the higher dose. Adverse events occurred more frequently with combination therapy than placebo, but were generally described as mild to moderate in severity and rarely led to withdrawal.
AUTHORS' CONCLUSIONS
Single dose oxycodone is an effective analgesic in acute postoperative pain at doses over 5 mg; oxycodone is two to three times stronger than codeine. Efficacy increases when combined with paracetamol. Oxycodone 10 mg plus paracetamol 650 mg provides good analgesia to half of those treated, comparable to commonly used non-steroidal anti-inflammatory drugs, with the benefit of longer duration of action.
Topics: Acetaminophen; Acute Disease; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Synergism; Drug Therapy, Combination; Humans; Oxycodone; Pain, Postoperative; Randomized Controlled Trials as Topic
PubMed: 19588335
DOI: 10.1002/14651858.CD002763.pub2 -
Psychopharmacology Dec 2022Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like...
RATIONALE
Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial μ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway.
OBJECTIVES
Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020).
METHODS
Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride.
FINDINGS
Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related.
CONCLUSIONS
Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.
Topics: Animals; Rats; Analgesics, Opioid; Mitragyna; Oxycodone; Plant Extracts; Receptors, Opioid; Secologanin Tryptamine Alkaloids
PubMed: 36308562
DOI: 10.1007/s00213-022-06244-z -
Addiction (Abingdon, England) Sep 2021To establish and quantify the association between abuse-deterrent formulation (ADF) oxycodone and 1-year risk of opioid-related harm.
AIM
To establish and quantify the association between abuse-deterrent formulation (ADF) oxycodone and 1-year risk of opioid-related harm.
DESIGN
Propensity score-matched cohort study of electronic medical records for years 2014-18, with patients followed up for 1 year after their index health-care visit.
SETTING
More than 70 million patients from 56 US health-care organizations.
PARTICIPANTS
Patients aged 18-64 years at index health-care visit with any indication for an oral opioid analgesic, with no past 12-month history of oral oxycodone use or substance use disorder, and who were alive at the end of the 1-year follow-up (new episode of prescription oral ADF oxycodone [OxyContin], n = 45 045; new episode of non-ADF oxycodone opioid preparation, n = 1 377 359).
MEASUREMENTS
International Classification of Diseases diagnoses of any opioid-related disorder or non-fatal opioid poisoning within 1 year of the index health-care visit. Pooled odds ratios (OR) with 95% confidence intervals (95% CI).
FINDINGS
After propensity score matching, 89 802 patients with a mean age of 44 [standard deviation (SD) = 11] years (62% women, 68% white) were included. During 1-year follow-up, 1445 diagnoses of opioid use disorder or opioid poisoning occurred in the ADF oxycodone cohort (34.8/1000 person-years) and 765 occurred in the non-ADF oxycodone cohort (18.2/1000 person-years). The odds of opioid-related adverse outcomes were increased in the ADF oxycodone cohort compared with the non-ADF oxycodone opioid cohort, including for opioid use disorders (OR = 2.02; 95% CI = 1.83, 2.23) and opioid poisoning (OR = 1.64 95% CI = 1.35, 1.99).
CONCLUSIONS
Patients with a new prescription of abuse-deterrent formulation oxycodone may be at increased risk of opioid-related harm.
Topics: Analgesics, Opioid; Child; Cohort Studies; Delayed-Action Preparations; Electronic Health Records; Female; Humans; Male; Opioid-Related Disorders; Oxycodone
PubMed: 33394528
DOI: 10.1111/add.15392