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Background: Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, especially in the elderly population. Opioids, which are potent analgesics, have shown an extraordinary ability to reduce intense pain in many osteoarthritic clinical trials; however, there is an increased need for a study to integrate the reported outcomes and utilize them to achieve a better understanding. Herein, efficacy and safety aspects of opioids used to manage osteoarthritic pain were assessed and compared using a model-based meta-analysis (MBMA). Methods: To perform the analysis, a comprehensive database consisting of pain relief compounds with information on summary-level of efficacy over time, adverse events and dropout rates was compiled from multiple sources. MBMA was conducted using a nonlinear mixed-effects modeling approach. Results: The results of primary efficacy endpoint analysis indicated that the doses of oxycodone, oxymorphone, and tramadol required to produce 50% of the maximum effect were 47, 84, and 247 mg per day, respectively. Efficacytime course analysis showed that opioids had rapid time to efficacy onset, suggesting potentially powerful painrelieving effects. It was also found that gastrointestinal adverse events were the most opioid-associated and dosedependent adverse effects. In addition, the analysis revealed that opioids were well-tolerated at low to moderate doses. Conclusions: This MBMA provides clinically meaningful insights into the efficacy and safety profiles of oxycodone, oxymorphone, and tramadol. Resultantly, the presented framework analysis can have an impact in the clinic on drug development where it can guide: the optimization of doses of opioids required to manage osteoarthritic pain; the making of precise key decisions for the positioning of new drugs, and; the design of more efficient trials.

Oxycodone (OC) is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of OC concentrations in postmortem cases is complicated due to tolerance and overlapping concentrations for fatal and non-fatal levels. In this study, our aim was to develop and validate a method for OC and its three metabolites: noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM) in postmortem femoral blood. Our goal was to define reference concentrations for intoxications and non-intoxications and investigate metabolic ratios in different causes of death. A rapid LC–MS-MS method using protein-precipitated postmortem blood was developed. Lower limit of quantitation was 0.005 μg/g blood for all analytes; upper limit of quantitation was 1.0 μg/g for OC and NOC and 0.25 μg/g for OM and NOM. The method displayed high precision (3.3–7.7%) and low bias (−0.3 to 12%). In total, 192 cases were analyzed and concentrations ranged from 0.005 to 13 μg/g for OC, 0.005 to 2.0 μg/g for NOC, 0.005 to 0.24 μg/g for OM, and 0.005 to 0.075 μg/g for NOM. We found a significant difference in OC concentration between the cases where OC contributed and those where it did not. In spite of that, we do not recommend the use of a specific blood concentration to distinguish fatal intoxications. Instead, the percentiles from our data set suggest that concentrations >0.2 μg/g are likely to have contributed to toxicity, but that concentrations as high as 0.3 might be tolerated without toxic effects. In addition, we also found that a low NOC/OC ratio could point toward an acute fatal intoxication. In conclusion, the OC concentration alone may not be sufficient to diagnose a fatal intoxication.

Oxycodone is a strong opioid frequently used as an analgesic. Although proven efficacious in the management of moderate to severe acute pain and cancer pain, use of oxycodone imposes a risk of adverse effects such as addiction, overdose, and death. Fast and accurate determination of oxycodone blood concentration would enable personalized dosing and monitoring of the analgesic as well as quick diagnostics of possible overdose in emergency care. However, in addition to the parent drug, several metabolites are always present in the blood after a dose of oxycodone, and to date, there is no electrochemical data available on any of these metabolites. In this paper, a single-walled carbon nanotube (SWCNT) electrode and a Nafion-coated SWCNT electrode were used, for the first time, to study the electrochemical behavior of oxycodone and its two main metabolites, noroxycodone and oxymorphone. Both electrode types could selectively detect oxycodone in the presence of noroxycodone and oxymorphone. However, we have previously shown that addition of a Nafion coating on top of the SWCNT electrode is essential for direct measurements in complex biological matrices. Thus, the Nafion/SWCNT electrode was further characterized and used for measuring clinically relevant concentrations of oxycodone in buffer solution. The limit of detection for oxycodone with the Nafion/SWCNT sensor was 85 nM, and the linear range was 0.5-10 mu M in buffer solution. This study shows that the fabricated Nafion/SWCNT sensor has potential to be applied in clinical concentration measurements.

Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced antinociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid antinociception in cancer-induced bone pain in female BALB/c mice and chemotherapy-induced peripheral neuropathy in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours, pain behaviors were evaluated after analgesic drug treatment. Heat shock protein 90 inhibition in the brain or systemically completely blocked morphine and oxymorphone antinociception in chemotherapy-induced peripheral neuropathy; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin antinociception. We also found that the Hsp90 isoform Hsp90α and the cochaperone Cdc37 were responsible for the observed changes in opioid antinociception. By contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid antinociception in cancer-induced bone pain. These results demonstrate that Hsp90 inhibitors block opioid antinociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.

To avoid a positive urine drug test, donors might try to subvert the test, either by adulterating the specimen with a product designed to interfere with testing or by substituting the specimen for a synthetic urine. A market search conducted in December of 2020 identified 3 adulterants and 32 synthetic urines, and a selection was procured based on specific criteria. Samples prepared with the 3 adulterants and 10 synthetic urines were submitted for testing at five forensic drug testing laboratories to perform immunoassay screening, chromatographic confirmation analysis and specimen validity testing (SVT). One adulterant determined to contain iodate reduced THC-COOH concentrations by 65% and the concentrations of 6-acetylmorphine, morphine, oxycodone, oxymorphone, hydrocodone and hydromorphone by 6–27%. Another adulterant determined to contain nitrite reduced THC-COOH concentrations by 22%, while the third did not affect drug screening or confirmatory testing. Both active adulterants could be identified through positive oxidant screens as well as through signal suppression in cloned enzyme donor immunoassay (CEDIA). The synthetic urines could not be identified either through traditional SVT or by the AdultaCheck10 dipstick. The Synthetic UrineCheck dipstick produced a difference in response between the authentic urine specimen and the synthetic urine samples, but the difference was small and difficult to observe. While most synthetic urines now contain uric acid, magnesium and caffeine, the results indicated that a biomarker panel including endogenous and exogenous markers of authentic urine performed well and clearly demonstrated the absence of biomarkers in the synthetic urines. The SVT assay also offers potential targets for future screening assays.

Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified

Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 hours before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and shamoperated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pretreatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.

The purpose of this research was to develop and validate an analytical method for the detection and quantification of noroxymorphone-3s-D-glucuronide, oxymorphone-3s-D-glucuronide, noroxymorphone, oxymorphone, 6α-oxycodol, 6β-oxycodol, noroxycodone, and oxycodone in urine by liquid chromatography tandem mass spectrometry (LC-MS/MS) to be used in a human study. The method was validated according the Academy Standards Board (ASB) Standard Practices for Method Development in Forensic Toxicology. The method was then applied to a single dose pilot study of a subject. Urine samples were collected from the subject after ingesting 10 mg oxycodone as an immediate release tablet. Additionally, urine specimens (n=15) had previously been confirmed positive for oxycodone were analyzed using validated method. The calibration range for noroxymorphone-3s-D-glucuronide and oxymorphone-3s-D-glucuronide was 0.05-10 µg/mL, for all other analytes it was 0.015-10 µg/mL. Validation parameters such as bias, precision, carryover, dilution integrity all met validation criteria. After the method was validated, urine samples from the first subject in the controlled dose study were analyzed. It was observed that oxycodone, noroxycodone and oxymorphone-3s-D-glucuronide contained the highest concentrations and were present in either the 0.5 or 1 h void. Noroxycodone and oxymorphone-3s-D-glucuronide were detected until the 48 h sample, while oxycodone was detectable till the 24 h sample. Tmax in urine was achieved within 1.5 h for oxycodone and within 3 h for noroxycodone and oxymorphone-3s-D-glucuronide. Cmax in urine for oxycodone, noroxycodone, and oxymorphone-3s-D-glucuronide was 3.15, 2.0, and 1.56 µg/mg, respectively. Oxycodone concentrations in authentic urines ranged from 0.015-12 µg/mL. Ranges for noroxymorphone-3s-D-glucuronide and oxymorphone-3s-D-glucuronide were 0.054-9.7 µg/mL and 0.14-67 µg/mL, respectively. A comprehensive method for the quantification of noroxymorphone-3s-D-glucuronide, oxymorphone-3s-D-glucuronide, noroxymorphone, oxymorphone, 6α-oxycodol, 6β-oxycodol, noroxycodone, and oxycodone in urine was optimized and met validation criteria. The concentrations of noroxymorphone-3s-D-glucuronide and oxymorphone-3s-D-glucuronide presented in this study provide details needed in the forensic community to better comprehend oxycodone pharmacokinetics.

Understanding the in-sewer stability of analgesic biomarkers is important for interpreting wastewater-based epidemiology (WBE) data to estimate community-wide analgesic drugs consumption. The in-sewer stability of a suite of 19 analgesics and their metabolites was assessed using lab-scale sewer reactors. Target biomarkers were spiked into wastewater circulating in simulated gravity, rising main and control (no biofilm) sewer reactors. In-sewer transformation was observed over a hydraulic retention time of 12 h. All investigated biomarkers were stable under control reactor conditions. In gravity sewer conditions, diclofenac, desmetramadol, ibuprofen carboxylic acid, ketoprofen, lidocaine and tapentadol were highly stable (0–20% transformation in 12 h). Valdecoxib, parecoxib, etoricoxib, indomethacin, naltrexone, naloxone, piroxicam, ketoprofen, lidocaine, tapentadol, oxymorphone, hydrocodone, meperidine, hydromorphone were considered as moderately stable biomarkers (20–50% transformation in 12 h). Celecoxib and sulindac were considered unstable biomarkers (>50% transformation in 12 h). Ketoprofen, lidocaine, tapentadol, meperidine, hydromorphone were transformed to 0–20% whereas diclofenac, desmetramadol, ibuprofen carboxylic acid, valdecoxib, parecoxib, etoricoxib, indomethacin, naltrexone, piroxicam were transformed up to 20–50% in 12 h in rising main reactor (RMR). These biomarkers were considered as highly stable and stable biomarkers in RMR, respectively. Sulindac, celecoxib, naloxone, oxymorphone and hydrocodone were transformed more than 50% in 12 h and considered as unstable biomarkers in RMR. This study provides the information for a better understanding of the in-sewer loss of the analgesics before using them in WBE biomarkers for estimating drug loads at the population level.

CONTEXT: Older adults are less likely than younger adults to receive naloxone therapy. Given high rates of prescription opioid use/misuse and increasing illicit opioid use among older adults, factors associated with naloxone administration for older opioid poisoning cases need examination. METHODS: We analyzed the 83,135 opioid-involved cases aged 50+ from the 2015–2020 National Poison Data System. Single-variable logistic regression was used to examine associations of naloxone administration with demographic factors, exposure site/reason, medical outcomes, management site/level of care, clinical effects, and other interventions. Multivariable logistic regression models were fit to examine associations of naloxone administration with different types of opioids. RESULTS: Over the six years, the proportion of prescription opioid cases that received naloxone therapy increased steadily from 21.9% to 28.4%. The proportion of illicit opioid cases that received naloxone therapy was 51.9% in 2015 and 59.8% in 2020 with a high of 64.4% in 2019. In 2020, the death rate for illicit opioid cases without naloxone therapy was 31.4% compared to 2.3% for those with the therapy. Cases managed at healthcare facilities (HCF) had higher odds of receiving naloxone therapy. Among prescription opioid cases, naloxone therapy rates among older and female cases and those managed at non-HCF settings were especially low even for major medical outcomes. Cases involving oxycodone, morphine, methadone, prescription fentanyl, hydromorphone, oxymorphone, and other/unknown opioids had higher odds of naloxone administration. DISCUSSION: Rates of naloxone therapy for older prescription opioid poisoning cases need improvement. While rates were higher among illicit opioid cases, the drop in 2020 and the sharp increase in deaths among illicit opioid cases without naloxone therapy confirm the importance of access to this life-saving intervention. CONCLUSIONS: Increased naloxone co-prescribing and other means of facilitating access to naloxone are needed to prevent opioid poisoning deaths among older adults who use prescription opioids.

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.

There is a need to develop a novel analgesic for pain associated with interstitial cystitis/painful bladder syndrome (IC/PBS). The use of the conventional μ-opioid receptor agonists to manage IC/PBS pain is controversial due to adverse CNS effects. These effects are attenuated in benzylideneoxymorphone (BOM), a low-efficacy μ-opioid receptor agonist/δ-opioid receptor antagonist that attenuates thermal pain and is devoid of reinforcing effects. We hypothesize that BOM will inhibit bladder pain by attenuating responses of urinary bladder distension (UBD)-sensitive afferent fibers. Therefore, the effect of BOM was tested on responses of UBD-sensitive afferent fibers in L6 dorsal root from inflamed and non-inflamed bladder of rats. Immunohistochemical (IHC) examination reveals that following the induction of inflammation there were significant high expressions of μ, δ, and μ-δ heteromer receptors in DRG. BOM dose-dependently (1–10 mg/kg, i.v) attenuated mechanotransduction properties of these afferent fibers from inflamed but not from non-inflamed rats. In behavioral model of bladder pain, BOM significantly attenuated visceromotor responses (VMRs) to UBD only in inflamed group of rats when injected either systemically (10 mg/kg, i.v.) or locally into the bladder (0.1 ml of 10 mg/ml). Furthermore, oxymorphone (OXM), a high-efficacy μ-opioid receptor agonist, attenuated responses of mechanosensitive bladder afferent fibers and VMRs to UBD. Naloxone (10 mg/kg, i.v.) significantly reversed the inhibitory effects of BOM and OXM on responses of bladder afferent fibers and VMRs suggesting μ-opioid receptor-related analgesic effects of these compounds. The results reveal that a low-efficacy, bifunctional opioid-based compound can produce analgesia by attenuating mechanotransduction functions of afferent fibers innervating the urinary bladder.

Oxycodone is used as a potent analgesic medication. Oxycodone is extensively metabolized. To fully describe its metabolism, the oxygenation of oxycodone to oxycodone N-oxide was investigated in hepatic preparations. The hypothesis tested was that oxycodone N-oxygenation was enzymatic and the amount of N-oxide detected was a consequence of both oxygenation and retro-reduction. Methods for testing the hypothesis included both in vitro and in vivo studies. Results indicated that oxycodone was N-oxygenated by the flavin-containing monooxygenase. Oxycodone N-oxide is chemically quite stable but in the presence of hepatic preparations and NADPH was retro-reduced to its parent compound oxycodone. Subsequently, oxycodone was metabolized to other metabolites including noroxycodone, noroxymorphone, and oxymorphone via cytochrome P-450. Retro-reduction of oxycodone N-oxide to oxycodone was facilitated by quinone reductase, aldehyde oxidase, and hemoglobin but not to a great extent by cytochrome P-450 or the flavin-containing monooxygenase. To confirm the in vitro observations, oxycodone was administered to rats and humans. In good agreement with in vitro results, substantial oxycodone N-oxide was observed in urine after oxycodone administration to rats and humans. Administration of oxycodone N-oxide to rats showed substantial amount of recovered oxycodone N-oxide. In vivo, noroxycodone was formed as a major rat urinary metabolite from oxycodone N-oxide presumably after retro-reduction to oxycodone and oxidative N-demethylation. To a lesser extent, oxycodone, noroxymorphone, and oxymorphone were observed as urinary metabolites. SIGNIFICANCE STATEMENT: This manuscript describes the N-oxygenation of oxycodone in vitro as well as in small animals and humans. A new metabolite was quantified as oxycodone N-oxide. Oxycodone N-oxide undergoes extensive retro-reduction to oxycodone. This re-establishes the metabolic profile of oxycodone and introduces new concepts about a metabolic futile cycle related to oxycodone metabolism.

Aim: Marijuana use has been postulated to modulate opioid use, dependence and withdrawal. Broad target drug testing results provide a unique perspective to identify any potential interaction between marijuana use and opioid use. Materials & methods: Using a dataset of approximately 800,000 urine drug test results collected from pain management patients of a time from of multiple years, creatinine corrected opioid levels were evaluated to determine if the presence of the primary marijuana marker 11-nor-carboxy-tetrahydrocannabinol (THC-COOH) was associated with statistical differences in excreted opioid concentrations. Results & conclusion: For each of the opioids investigated (codeine, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl and buprenorphine), marijuana use was associated with statistically significant lower urinary opiate levels than in samples without indicators of marijuana use.

Opioids, both as prescription drugs and abuse substances, have been a hot topic and a focus of discussion in the media for the last few years. Although the literature published shows the occurrence of opioids and some of their metabolites in the aquatic environment, there are scarce data in the application of high resolution mass spectrometry (HRMS) for the analysis of these compounds in the environment. The use of HRMS allows increasing the number of opioids that can be studied as well as the detection of unknown opioids, their metabolites and potential transformation products. In this work, a retrospective analysis for the identification of opioids and their metabolites using a curated database was applied to surface water and wastewater samples taken in the state of Minnesota (U.S.) in 2009, which were previously analyzed by liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS) for antidepressants. The database comprised >200 opioids including natural opiates (e.g. morphine and codeine), their semi-synthetic derivatives (e.g. heroin, hydromorphone, hydrocodone, oxycodone, oxymorphone, meperidine and buprenorphine), fully synthetic opioids (e.g. fentanyl, methadone, tramadol, dextromethorphan and propoxyphene), as well as some of their metabolites (e.g. 6-monoacetylcodeine, dextrorphan, EDDP, normorphine and O-desmethyltramadol). Moreover, additional MS-MS experiments were performed to confirm their identification, as well as to recognize fragmentation patterns and diagnostic ions for several opioids. These data provide a better understanding of the historical occurrence of opioids and their metabolites in surface waters impacted by wastewater sources. The concentrations of individual opioids in surface water and wastewater effluent varied from 8.8 (EDDP) to 1640 (tramadol) ngL-1 and from 12 (dihydrocodeine) to 1288 (tramadol) ngL-1, respectively. The opioids with higher overall frequency detections were tramadol, dextromethorphan and its metabolite, dextrorphan.

The United States is enduring a preventable opioid crisis, particularly involving a population being treated in a hospital setting, a subset of whom may escalate to illicit opioids. This project analyzed trends in distribution of opioids by hospitals in the United States. Opioids monitored included buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, powdered opium, remifentanil, and tapentadol. The Automation of Reports and Consolidated Orders System (ARCOS) reports on substances controlled by the Drug Enforcement Administration. National data from ARCOS reports 5 and 7 from 2000 to 2019 were used for an observational study on hospital opioid distribution. Morphine milligram equivalents (MMEs) were calculated using oral conversion factors. The MME per person per state was calculated to compare data from the peak year, 2012, with data from 2019. Opioid use peaked in 2012, with a -46.6% decline from 2012 to 2019. Half (25) of the states have seen a decrease of -50% or greater. Of the opioid compounds observed, buprenorphine has seen increased (+122.5%) hospital use from 2012 to 2019. All other opioids have been experiencing a decline (≥50%), particularly hydromorphone (-49.9%), oxymorphone (-57.7%), methadone (-58.7%), morphine (-66.9%), codeine (-67.5%), and meperidine (-77.6%). There was a 6-fold difference in population-corrected use of opioids in 2019 between the lowest (6.8 MME/person in New Jersey) and highest (Alaska = 39.6) states. This study demonstrates the considerable progress made thus far by hospitals in curbing the U.S. opioid crisis.

The United States is enduring a preventable opioid crisis, particularly involving a population specifically being treated in a hospital setting. This project analyzed trends in distribution of opioids by hospitals in the United States from 2000 to 2019. Opioids monitored included buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, powdered opium, remifentanil, and tapentadol. The Automation of Reports and Consolidated Orders System (ARCOS) reports controlled substances via the Drug Enforcement Administration (DEA). Data from ARCOS reports 5 and 7 from 2000 to 2019 were utilized for an observational study on hospital opioid distribution in the US. Morphine milligram equivalents (MME) were calculated using oral conversion factors for each opioid. The MME per person per state was calculated to compare data from the peak year, 2012, to data from 2019. Opioid use in the United States peaked in 2012 with a 46.6% decline from 2012 to 2019. Within the US, 25 of 50 states have seen a decrease of 50% or greater. Of the opioid compounds observed, buprenorphine has seen increased (123%) hospital use from 2000 to 2019. All other opioids have been experiencing a slow decline (>40%) in hospital use since that time. This study demonstrated the progress made thus far by hospitals in curbing the US opioid epidemic.

Background: Previous data suggest that tapentadol, an atypical opioid with a putative dual mechanism of action, has relatively low rates of abuse. A better understanding of the rates of abuse among different prescription opioids may help clinicians when considering their potential risks and benefits. The results of urine drug tests (UDTs) may provide a unique opportunity to help answer this question. Method: To investigate different rates of prescription-opioid abuse in this retrospective study, we examined urine drug test results from patients seeking treatment at four facilities of an opioid-use-disorder (OUD) treatment program in Ohio. Urine specimens were collected on admission, one from each patient, in the regular course of care. The opioids reviewed in the present study were tapentadol, hydrocodone, oxycodone, hydromorphone, oxymorphone, and tramadol. Drug dispensing data, including morphine-milligram equivalents (MME) dispensed, were examined to adjust for the relative prevalence of each opioid being examined. Results: Data from 4,162 patients were examined. Tapentadol was the least common finding in UDT results in this cohort and remained so after adjusting for drug availability. The percentage of specimens positive for a given opioid ranged from 0.12 percent (tapentadol) to 7.04 percent (oxycodone). The availability and MME adjustments resulted in a change of rank order, with tapentadol remaining the lowest but tramadol replacing oxycodone as the prescription opioid with the highest rate of abuse. Conclusions: In this sample of UDT results from patients seeking treatment at an OUD program in Ohio, tapentadol was the least frequent finding among the opioids examined, and this remained true when adjusting for dispensing data. Factors potentially contributing to this difference may include pharmacological properties unique to tapentadol. Several important limitations notwithstanding, these findings are consistent with previous real-world evidence and warrant an ongoing line of inquiry.

The C-3 phenolic hydroxy group containing morphine derivatives (morphine, oxymorphone, naloxone, naltrexone) are excellent candidates for the synthesis of 3-O-functionalized molecules. Achieving free carboxylic group containing derivatives gives the opportunity for further modification and conjugation that could be used for immunization and immunoassays. For this purpose ethyl bromo- and chloroacetate can be used as O-alkylating agents. Hydrolyzing the products affords the appropriate free carboxylic group containing 3-O-carboxyalkyl derivatives. As these molecules contain an acidic and a basic functional group the protonation macro- and microconstants were determined too, using pH-potentiometry and NMR-pH titration, beside fully characterizing their structure using IR, CD, NMR and HR-MS measurements.

The objective of this study was to develop and validate a highly sensitive method for the detection of oxycodone, noroxycodone, 6?-oxycodol, 6?-oxycodol, oxymorphone, and noroxymorphone in blood by liquid chromatography tandem mass spectrometry. The analytes were extracted from blood (0.5 mL) using Bond Elut Certify Solid Phase Extraction columns, evaporated to dryness and reconstituted before analysis was performed on an Acquity UPLC? I-class coupled to a Waters Xevo TQD. Academy Standards Board Standard Practices for Method Development in Forensic Toxicology were used for the validation of this method. The limit of quantitation for all analytes was established at 0.5 ng/mL. Calibration range for noroxymorphone, oxymorphone, 6?-oxycodol and 6?-oxycodol was 0.5?25 ng/mL and 0.5?100 ng/mL for noroxycodone and oxycodone. Precision (2.90?17.3%) and bias studies resulted in a ?15% deviation. There were no interferences observed from internal standard, matrix, or common drugs of abuse. Stability of all analytes at two concentrations at 24, 48, and 72 h in the autosampler did not exceed ?20% difference from the initial T0. Dilution integrity at a ten-fold dilution was acceptable as analyte concentrations ranged between (?18%) of the target concentration. Once validated, the method was used in a pilot dosing study of one male subject after taking a 10 mg immediate release tablet of oxycodone. Blood samples were collected at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 9, and 24 h after ingestion. Oxycodone and noroxycodone both reached Tmax at 1.5 h and had Cmax values of 25.9 and 12.8 ng/mL, respectively. Oxycodone, 6?-oxycodol, and 6?-oxycodol were detectable up to 9 h, while noroxymorphone and noroxycodone were still detected at 24 h. Funding Agencies|Strategic Research Area in Forensic Sciences at University of Linkoping, Sweden [304399, 304774]

Introduction: A range of opioids are commonly prescribed to manage chronic pain, but individual patient responses vary greatly, especially in older populations. One source of that variability are differences in absorption, metabolism and excretion, i.e. pharmacokinetics. Blood, plasma and serum concentrations of opioids allow that variability to be quantified and may be used to optimise opioid dosing. As an aid to that process, there is an unmet need to rapidly quantify several opioids and their metabolites in a single analytical method. Aims: To develop a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for simultaneous quantification of tramadol, oxycodone, fentanyl and their major metabolites in various human matrices. Methods: Sample preparation involved adding three deuterated internal standards followed by protein precipitation with 100 % acetonitrile, evaporation and reconstitution. Separation of analytes via LC was achieved on a reversed phase column via binary gradient elution using 0.005 % formic acid in water and 100 % acetonitrile as mobile phases. Analytes were detected via MS/MS with multiple reaction monitoring (MRM). Results: The method was accurate with the inter-day and intra-day accuracy of quality control samples (QCs) below 15 %. It was also precise with inter-day and intra-day coefficient of variation below 15 %. The lower limit of quantification (LLOQ) was 0.2 ng/mL for all analytes except tramadol and its metabolites, where the LLOQ was 10 ng/mL. Recovery was greater than 88 % for all analytes, except for O-desmethyltramadol (81 %). Analytes were stable over four freeze-thaw cycles, for 24 h on the bench top and for 24 h post-preparation. The inter- and intra-day variability of concentrations determined in blood and plasma were within 84–124%, whereas the inter- and intra-day variability for blood samples prepared using volumetric absorptive micro-sampling (VAMS) compared to those prepared from whole blood ranged between 83–122%. Conclusion: A LC–MS/MS method is described that is able to accurately and precisely quantify a number of commonly prescribed opioids and their major metabolites in plasma and whole blood, including whole blood collected using VAMS. Refereed/Peer-reviewed

Here we describe the dataset of the first report of pharmacogenomics profiling in an outpatient spine setting with the primary aims to catalog: 1) the genes, alleles, and associated rs Numbers (accession numbers for specific single-nucleotide polymorphisms) analysed and 2) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications. The present description applies to analgesic medication-metabolizing enzymes and may be especially valuable to investigators who are exploring strategies to optimize pharmacologic pain management (e.g., by tailoring analgesic regimens to the genetically identified sensitivities of the patient). Buccal swabs were used to acquire tissue samples of 30 adult patients who presented to an outpatient spine clinic with the chief concern of axial neck and/or back pain. Array-based assays were then used to detect the alleles of genes involved in the metabolism of pain medications, including all common (wild type) and most rare variant alleles with known clinical significance. Both CYP450 isozymes - including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 - and the phase II enzyme UDP-glucuronosyltransferase-2B7 (UGT2B7) were examined. Genotypes/phenotypes were then used to evaluate each patient's relative ability to metabolize 37 commonly used analgesic medications. These medications included both non-opioid analgesics (i.e., aspirin, diclofenac, nabumetone, indomethacin, meloxicam, piroxicam, tenoxicam, lornoxicam, celecoxib, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, naproxen, and mefenamic acid) and opioid analgesics (i.e., morphine, codeine, dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, alfentanil, fentanyl, sufentanil, meperidine, ketobemidone, dextropropoxyphene, levacetylmethadol, loperamide, methadone, buprenorphine, dextromethorphan, tramadol, tapentadol, and tilidine). The genes, alleles, and associated rs Numbers that were analysed are provided. Also provided are: 1) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications and 2) the mechanisms of metabolism of the analgesic medications by primary and ancillary pathways. In supplemental spreadsheets, the raw and analysed pharmacogenomics data for all 30 patients evaluated in the primary research article are additionally provided. Collectively, the presented data offer significant reuse potential in future investigations of pharmacogenomics for pain management.

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.

Cancer pain About 10%–15% of adults experience some chronic pain.1 The prevalence is considerably higher in certain populations like cancer, where pain affects more than two-thirds with advanced disease and one-third after curative treatment.2 Roughly one-third of ambulatory patients with solid tumours experiencing pain achieve significant pain reduction while one-fifth experience pain deterioration using conventional strategies within 1 month of initial assessment.3 Uncontrolled pain negatively affects quality of life and may reduce survival.4 Inadequate pain relief may be due to infrequent monitoring, lack of knowledge regarding opioid pharmacology, minority race, older age and pain assessment failure.3 ### Genetics and variability in opioid responses Opioids are recommended for first-line treatment of moderate to severe pain. However, there is large interindividual variability in response. Data suggest pharmacogenomics may partially explain this, where genetic differences affect opioid pharmacokinetics and pharmacodynamics.5 6 Over 90% of patients have pharmacogenetic variant(s) which impact drug responses and over one-fourth a variant that may contribute to opioid response.7 The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published more than 45 drug-specific, peer-reviewed guidelines on how to best apply pharmacogenomics to guide therapy (more than a dozen relate to supportive care, including opioids).8 Integration of pharmacogenetic-guided treatment pathways can personalise drug selection in supportive oncology and help determine the magnitude of drug–drug and drug–drug–gene interactions.5 6 Table 1 summarises key genes and their clinical implications on opioid response. View this table: Table 1 Opioid pharmacogenomics summary ### Actionable genes: Cytochrome P450 2D6 Cytochrome P450 2D6 (CYP2D6) hepatically metabolises codeine, hydrocodone, oxycodone and tramadol to more potent metabolites: morphine, hydromorphone, oxymorphone and o-desmethyltramadol, respectively. CYP2D6 gene polymorphisms alter enzyme activity and can affect opioid response.5 6 It is expected that 8%–10% of the general population are poor metabolisers (PMs), 4%–6% ultrarapid metabolisers (UMs) and 25%–30% intermediate metabolisers (IMs) (frequencies vary depending on race/ethnicity).9 Codeine-related fatalities in children with the CYP2D6 …

Oxymorphone's metabolism does not involve the hepatic cytochrome P450 (CYP) system. The effect of this pharmacokinetic feature of oxymorphone on opioid prescribing is unknown.To assess the relative frequency with which oxymorphone and oxycodone (a CYP3A-metabolized opioid analgesic) were each prescribed to patients concomitantly receiving CYP3A-modifying drugs (i.e., inducers and inhibitors) to characterize opioid-prescribing patterns in patients at risk for CYP3A-related drug interactions.We analyzed the Sentinel Distributed Database from January 1, 2013, to December 31, 2016, to identify the proportion of patients with concomitant dispensing of selected CYP3A modifiers among initiators of oxymorphone. We then repeated the analysis using oxycodone instead of oxymorphone. We conducted sensitivity analyses that varied the washout periods for each opioid to account for potential opioid switching.In the primary analysis, the proportion of patients with concomitant incident dispensings of oxymorphone and selected CYP3A modifiers was 3.26% (95% CI = 3.09%-3.43%), and the proportion of patients with incident dispensings of oxycodone and selected CYP3A modifiers was 2.82% (95% CI = 2.79%-2.85%). The difference between proportions was 0.43% (95% CI = 0.26%-0.60%). Sensitivity analyses that varied the washout periods for each opioid with respect to the other opioid to account for switching yielded similar results.We observed similar proportions of patients using selected CYP3A modifiers concomitantly with both oxymorphone and oxycodone. While the CIs of the point estimates did not overlap, the absolute differences between the proportions were small.This project was supported by Task Order HHSF22301001T under Master Agreement HHSF223201400030I from the U.S. Food and Drug Administration (FDA). The FDA approved the study protocol, including the statistical analysis plan, and reviewed and approved the manuscript. Coauthors from the FDA participated in the results interpretation and in the preparation and decision to submit the manuscript for publication. Coyle, Money, Staffa, Meyer, and Woods are employed by the FDA. The other authors have no financial conflicts of interest to report. The views expressed are those of the authors and not necessarily those of the U.S. Department of Health and Human Services, U.S. Food and Drug Administration.

Background Cancer patients often require feeding or venting gastrostomy-tubes (G-tubes) for enteral nutrition or symptom palliation. The administration of most extended-release (ER) opioids via the G-tube or orally followed by clamping of the venting G-tube is contraindicated. Oxymorphone immediate release (IR) may be useful because of its longer half-life compared to other IR opioids. We examined the use of oxymorphone IR administered every 8 hours in patients with G-tubes. Methods This was a retrospective chart review of 40 consecutive cancer patients with G-tubes who underwent opioid rotation (OR) to oxymorphone. Demographics, symptoms, morphine equivalent daily dose (MEDD), and oxymorphone dose were collected. Successful OR was defined as a 2-point or 30% reduction in pain score and continued use of oxymorphone at follow-up in outpatient setting, or discharge in inpatient setting. Opioid rotation ration (ORR) between MEDD and oxymorphone in patients with successful OR was calculated as MEDD before the OR divided by total oxymorphone dose/day at follow-up or discharge. Results The median age was 56 years, 57.5% were white, 68% male, 47.5% (n=19) had head and neck cancer, 90% had advanced disease, 67.5% (n=27) were inpatient, and 15% (n=6) had venting G-tubes. 25/40 (62.5%) patients had successful OR to oxymorphone. The median ORR from MEDD to oxymorphone was 3.5 (IQR, 3.1-4). There were no independent predictors for successful OR, and ORR did not significantly differ among various groups. Conclusions Oxymorphone IR can be used successfully in cancer patients with G-tubes using an ORR of 3.5 to calculate dose from MEDD.

Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at μ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other μ opioid receptor agonists.The current study compared the acute behavioral effects of BOM with the effects of other μ opioid receptor agonists.Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration.BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration.Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by μ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.

Over 100 million Americans suffer from chronic pain. Therefore, proper pain management is essential for well-being of these patients. Morphine and codeine are natural alkaloids present in opium. In addition to morphine and codeine, many semisynthetic opiates such as oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, and buprenorphine are synthesized from thebaine, a naturally occurring alkaloid present in opium. In addition, synthetic opioids, such as fentanyl, alfentanil, sufentanil, remifentanil, meperidine, methadone, levorphanol, pentazocine tramadol, and tapentadol, are routinely used in pain management patients. Unlike semisynthetic opioids that have structural similarity with morphine, synthetic opioid are not structurally related to morphine, but similar to morphine, synthetic opioids also interact with opioid receptors for their pharmacological action. In order to combat opioid misuse and abuse, pharmaceutic companies more recently have introduced abuse-deterrent formulations of opioids. Various approaches, such as physical/chemical barrier, formulating with opioid receptor antagonists such as naloxone or naltrexone, using an aversion agent to deter abuse, prodrug formulation, or subcutaneous delivery of opioid, have been utilized to marker abuse-deterrent opioid formulations.

The 36-year-old male patient was on 30 mg per day oxycodone prescription for chronic, nonmalignant pain but was found negative on the opiate urine drug screen by an immunoassay. Because of the low cross-reactivity of the opiate screening assay for oxycodone a confirmation test by liquid chromatography–tandem mass spectrometry (LC–MS/MS) was ordered that showed negative result as well. Drug diversion was suspected, and he was advised that his prescription oxycodone would be discontinued if he were found negative again. His next urine opiate immunoassay screen was strongly positive and the clinician suspected spiking of his urine. After consultation with the laboratory the opiate positive urine sample was tested for oxycodone and its metabolites by LC–MS/MS. The results showed oxycodone concentration >2000 ng/mL but undetectable noroxycodone and oxymorphone (both less than 20 ng/mL). While the initial negative opiate screening assay results could be explained by the poor cross-reactivity of the opiate assay with oxycodone, the more specific LC–MS/MS assay results confirmed diversion and sample spiking.