Search

A rapid, simple extraction method followed by qualitative screening using liquid chromatography-tandem mass spectrometry (LC-MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council's Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid-liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid-buffer mix collected in a Quantisal™ device, followed by LC-MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective To evaluate the pharmacokinetics, in dogs, of liposome-encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique ( ASG). Animals Four healthy purpose-bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg. Study design Randomized cross-over design. Methods Each dog was given either 4.0 mg kg−1 of ASG-oxymorphone or 8.0 mg kg−1 of ASG-hydromorphone SC on separate occasions with a 3-month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC- MS and pharmacokinetic parameters were calculated using commercial software and non-compartmental methods. Results Serum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. Cmax for ASG-oxymorphone was 7.5 ng mL−1; Cmax for ASG-hydromorphone was 5.7 ng mL−1. Conclusions and clinical relevance Oxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs. [ABSTRACT FROM AUTHOR]

This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence. [ABSTRACT FROM AUTHOR]

The N-oxide of O-acyloxymorphone, when treated with the Burgess reagent, provides the corresponding oxazolidine in a one-pot sequence and in excellent yield. The oxazolidine derived from oxymorphone, temporarily protected at O-3 and C-6, reacts with Grignard reagents to provide directly N-allyl, N-cyclopropylmethyl, and N-cyclobutylmethyl derivatives that are further converted to the title compounds, namely naltrexone, naloxone, nalbuphone, and nalbuphine in excellent yields. Each of these medicinal agents is obtained from the oxazolidine in a one-pot sequence. Complete spectral and experimental data are provided for all compounds. [ABSTRACT FROM AUTHOR]

The article presents a case study of 37-year-old male who was found supine and minimally responsive in basement of his mother's home and reported miotic pupils, depressed mental status and bradypnea which improved after administration of naloxone intramuscularly. Topics discussed include differential diagnosis of sensorineural hearing loss, denial of patient regarding previous episodes of hearing loss, and complete resolution of his bilateral hearing loss after five hours.

Thrombotic thrombocytopenic purpura (TTP) is an acute syndrome with varying clinical manifestations and approximately 5% of patients experiencing neurologic symptoms, fever and renal failure. The most notable drugs known to cause TTP include quinine, mitomycin, gemcitabine, cyclosporine, ticlopidine, and clopidogrel. Recently, a TTP-like illness has been associated with the intravenous abuse of oxymorphone with 15 cases reported in Tennessee. We report a patient who presented with a TTP-like illness and subsequently was re-admitted with grand-mal seizures and stroke-like symptoms. Upon reviewing her case, we determined that her symptoms were most likely associated with intravenous abuse of oxymorphone. [ABSTRACT FROM AUTHOR]

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., (Published by Oxford University Press 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Abstract: Background: The extent of prescription opioid abuse has led to the development of formulations that are difficult to crush. The purpose of the present studies was to examine whether experienced prescription opioid abusers (individuals using prescription opioids for non-medical purposes regardless of how they were obtained) were able to prepare a formulation of oxymorphone hydrochloride ER 40mg designed to be crush-resistant (DCR) for intranasal (Study 1) or intravenous abuse (Study 2), utilizing a non-crush-resistant formulation of oxymorphone (40mg; OXM) as a positive control. Methods: No drug was administered in these studies. Participants were provided with DCR and OXM tablets in random order and asked to prepare them for abuse with tools/solutions that they had previously requested. The primary outcome for Study 1 was particle size distribution, and the primary outcome for Study 2 was percent yield of active drug in the extracts. Other descriptive variables were examined to better understand potential responses to these formulations. Results: Fewer DCR than OXM particles were smaller than 1.705mm (9.8% vs. 97.7%), and thus appropriate for analyses. Percent yield of active drug in extract was low and did not differ between the two formulations (DCR: 1.95%; OXM: 1.29%). Most participants were not willing to snort (92%) or inject (84%) the tampered products. Participants indicated that they found less relative value in the DCR than the OXM formulation across both studies. Conclusions: These data suggest that the oxymorphone DCR formulations may be a promising technology for reducing opioid abuse. [Copyright &y& Elsevier]

Abstract: A selective high performance liquid chromatography–tandem mass spectrometric (LC–MS/MS) method for the simultaneous determination of oxymorphone and its active metabolite 6-OH-oxymorphone in human plasma was developed and validated using oxymorphone-d3 as the internal standard. Chromatographic conditions were optimized to separate oxymorphone from the other metabolite, oxymorphone-3-glucuronide, which may convert to oxymorphone in MS ion source, resulting in inaccurate quantitation of oxymorphone. Solid phase extraction (SPE) was used to extract oxymorphone and 6-OH-oxymorphone from plasma. SPE offered the advantage of being able to remove the unwanted metabolite, oxymorphone-3-glucuronide, through the wash step during the extraction. The developed method was precise and reproducible as shown by good linearity of calibration curves (correlation coefficients ≥0.9968 for oxymorphone and ≥0.9967 for 6-OH-oxymorphone) with high intraday assay and interday assay precision (CV% ≤11.0% for oxymorphone and ≤12.6% for 6-OH-oxymorphone) over a range of 35/25 – 5000/5000pg/mL for oxymorphone/6-OH-oxymorphone. The method has been successfully applied to analyze oxymorphone and 6-OH-oxymorphone in plasma from 19 healthy volunteers in a bioequivalence study. A total of 1026 samples were analyzed. Good linearity (average correlation coefficient 0.9988 for oxymorphone and 0.9966 for 6-OH-oxymorphone) was achieved with calibration curves and high precision (CV% ≤5.9% for oxymorphone and ≤10.9% for 6-OH-oxymorphone) was obtained with QCs. [Copyright &y& Elsevier]

Abstract: Adverse events may occur with an extended-release (ER) opioid if tampering or coadministration with ethanol causes excessive exposure (dose dumping) to the opioid. The effects of ethanol on the in vitro dissolution and in vivo pharmacokinetics of oxymorphone ER and oxymorphone crush-resistant formulation (CRF) were evaluated. In vitro dissolution rates were measured for oxymorphone ER 40-mg and oxymorphone CRF 40-mg tablets in aqueous solutions of 0 to 40% ethanol. In 2 in vivo, open-label, randomized, crossover studies, fasted healthy volunteers received single oral doses of oxymorphone ER 40 mg or oxymorphone CRF 40 mg with 240 mL of 0 to 40% ethanol. Naltrexone was used to minimize opioid effects. In the in vitro analyses, dissolution rates of oxymorphone ER and CRF were unaffected in aqueous solutions of ≤40% ethanol. Coadministration of oxymorphone ER or oxymorphone CRF with ethanol 20 and 40% increased oxymorphone peak plasma concentrations (Cmax) by 14 to 80% and reduced time to Cmax. For both formulations, oxymorphone area under the curve and terminal half-life were largely unaffected, but Cmax increased with ethanol dose. Neither oxymorphone formulation exhibited dose dumping in terms of overall exposure when coingested with ethanol. Perspective: Administering oxymorphone ER or oxymorphone CRF with 240 mL of ≤40% ethanol increased oxymorphone Cmax without dose dumping in terms of area under the curve. These results provide reassurance about the integrity of oxymorphone ER formulations with ethanol. Nonetheless, alcohol and opioids should never be combined because of the risk of respiratory depression. [Copyright &y& Elsevier]

Dr. Craig describes the drug's pharmacology, pharmacokinetics, efficacy, and safety; the process of switching from other agents; and ways pharmacists can help prevent abuse of this controlled substance. [ABSTRACT FROM AUTHOR]

Abstract: Opioids are recommended for control of moderate-to-severe, chronic, malignant, and nonmalignant pain. A controlled-release formulation of the opioid oxymorphone has recently been launched. The aim of this review was to assess the effectiveness of oxymorphone as an analgesic in chronic pain. A systematic search for published studies of oral oxymorphone in the management of chronic pain was conducted. The studies were evaluated for their internal validity according to standard criteria. They were also evaluated for their external validity and research ethic aspects. A meta-analysis was performed to examine the effect of oxymorphone compared with placebo. Nine studies were evaluated; three were excluded because of low quality. Six controlled studies (duration 2–12 weeks) included a total of 1489 subjects suffering from chronic low back pain, chronic pain from osteoarthritis, and chronic cancer pain. Three of the studies were of high quality and three of medium quality. External validity was assessed to be high, medium, and low (in one, three, and two studies, respectively). The meta-analysis suggests that daily doses of 40–100mg are superior to placebo; however, the estimate (reduction of pain intensity compared with placebo) of the treatment effect is imprecise (95% confidence interval −17.08, −8.69). Limited evidence suggests that oxymorphone is effective for pain control in patients with cancer. No significant differences between oxymorphone and oxycodone at equipotent doses were found. In conclusion, oxymorphone is superior to placebo. There is no evidence that the efficacy of oxymorphone differs from other opioids. [Copyright &y& Elsevier]

Abstract: Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients. The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1. Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0–12h of oxycodone by 19% (−23 to 113%; P =0.003), and that of noroxycodone by 100% (5–280%; P <0.0001) but decreased the AUC0–12h of oxymorphone by 67% (−100 to −22%; P <0.0001) and that of noroxymorphone by 68% (−100 to −16%; P <0.0001). Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P =0.0471) indicating that these adverse effects were due to paroxetine. No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied. The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6. [Copyright &y& Elsevier]

Abstract: Structure–activity relationships built around receptor binding or cell-based assays are designed to reveal physiochemical differences between ligands. We hypothesized that agonist receptor reserve may provide a unique approach to distinguish structurally-related agonists exhibiting similar functional characteristics. An intracellular calcium activation assay in Chinese Hamster Ovary (CHO) cells expressing cloned human μ-opioid receptors was developed. We examined two isomers exhibiting indistinguishable receptor binding and in vitro potency profiles. Oxymorphone, a clinically-available congener of codeine has at least two active diastereomeric metabolites (6α- and 6β-oxymorphols) found to be similar for μ-opioid receptor binding affinity (K d =15 versus 14 nM) and calcium activation (EC50 =22 versus 14 nM). Calcium activation was then inhibited in CHO cells in a concentration-dependent manner using the irreversible μ-opioid receptor antagonist, β-funaltrexamine (β-FNA). Under these conditions, ~10-fold greater receptor reserve was found for 6α-oxymorphol compared to 6β-oxymorphol. This difference between the oxymorphols corresponded to a rank order of intrinsic efficacy (Emax): DAMGO>oxymorphone=6α-oxymorphol=oxycodone>6β-oxymorphol. In addition, 6α-oxymorphol exhibited greater relative potency than the 6β-oxymorphol in mouse tail-flick, hot-plate and phenylquinone writhing antinociceptive assays, regardless of route of administration. Thus the β-FNA/calcium model provides a novel, cell-based approach to distinguish structurally related μ-opioid agonists, and in the specific case of the oxymorphols, receptor reserve differences provided a means to bridge functional in vitro and in vivo models. [Copyright &y& Elsevier]

To obtain the durable benefits of opioid analgesia, physicians must develop strategies to manage the negative attributes of opioid therapy. Side effects, opioid tolerance, and toxicity limit the use of opioids, yet specific guidelines have not emerged for appropriate doses. Furthermore, there are wide variations in interindividual responsiveness to opioid analgesia. Opioid rotation is an effective, emerging strategy to help manage the negative effects of opioids by limiting doses required to obtain pain relief with tolerable side effects. Tolerance to one particular type of opioid does not necessarily develop at the same rate as tolerance to another opioid (incomplete cross-tolerance). Side effects may vary and generally are reduced at lower doses. Oxymorphone is a highly potent molecule that offers linear dose proportionality, multiple preparations (IV, immediate release, extended release) and good analgesic effect. Strategies for rotating a patient from an opioid to oxymorphone require dose calculation based on equianalgesia, a conversion period and dose titration. In addition to converting a patient from other oral opioids to oxymorphone, special strategies are needed for particular preparations (extended release to extended release; extended release to immediate release to extended release; cross-titration; in-patient titration). Issues in opioid rotation involving oxymorphone are common to other opioid rotation plans: side effects, in particular nausea and constipation, as well as toxicity concerns. While pain patients present a unique challenge to physicians, opioid analgesia involving oxymorphone and opioid rotation strategies have been shown to be effective in pain management in some patients with tolerable side effects. [ABSTRACT FROM AUTHOR]

Multiple formulations exist to provide enteral controlled-release (CR) opioid delivery. An appreciation of these various delivery systems may provide clinicians with the knowledge to feel comfortable utilizing multiple different opioid CR formulations in their practices in efforts to optimize patient analgesia while minimizing adverse effects. [ABSTRACT FROM AUTHOR]

Oxymorphone (14-hydroxydihydromorphinone) is primarily a potent μ-opioid receptor agonist with oral immediate-release (IR) and extended-release (ER) formulations approved in the United States in 2006. The oral oxymorphone formulations are roughly three times more potent than oral morphine. It is more lipophilic than morphine and, thus, may more easily cross the blood-brain barrier because it differs from morphine having a ketone-group substituent at the C-6 position. Oxymorphone IR is indicated for the relief of moderate—to severe pain, while oxymorphone ER is indicated for persistent pain. Initial doses (opioid-naïve) are 10–20 mg every 4–6 hours (IR) and 5 mg every 12 hours (ER). Oxymorphone was found not to have any clinically significant cytochrome (CYP)3A4, CPY2C9, or CYP2D6 interactions, thus limiting its potential for causing some of the more common drug–drug interactions via the CYP450 system. The common adverse effects of oxymorphone are consistent with those commonly seen with other opioid, including nausea/vomiting, constipation, pruritis, pyrexia, somnolence, and sedation. [ABSTRACT FROM AUTHOR]

Oxymorphone extended release is a relatively recent addition to the clinical armamentarium of modified or continuous release opioid analgesics for the treatment of moderate to severe pain. This review provides an overview of published and certain internationally presented study data of efficacy, safety and tolerability. [ABSTRACT FROM AUTHOR]

Objective. Assess the effectiveness and tolerability of a program of gradual dose titration with oxymorphone extended release (ER) for treatment of moderate to severe chronic pain in opioid-naive patients. Design. Open-label, nonrandomized 6-month study with a titration/stabilization period of ≤1 month followed by a 5-month maintenance period. Setting. Multidisciplinary pain centers in the United States. Patients. Adult opioid-naive patients with moderate to severe chronic pain. Interventions. Patients were gradually titrated from a 5-mg dose of oxymorphone ER (taken every 12 hours) to a stabilized dose that provided effective pain relief and was well tolerated. Outcome Measures. Brief Pain Inventory Short Form questions 5 and 9, patient and physician global assessments of pain relief, adverse events (AEs), and discontinuations. Results. The majority (94/126; 75%) of patients were stabilized on a dose of oxymorphone ER that provided effective pain relief with tolerable AEs. Most (81/94; 86%) required <24 days to reach a stable dose. Sixteen percent of patients in the titration period and 17% of patients in the maintenance period discontinued because of AEs possibly or probably related to oxymorphone ER. Patients completing the entire 5-month maintenance period experienced effective pain relief with significant (>50%) reductions of pain interference with quality-of-life measures. There was minimal dose escalation over the 5 months and low use of rescue medication. Conclusions. Oxymorphone ER provided effective pain relief from moderate to severe chronic pain in opioid-naive patients. Gradual titration was well tolerated, with a low rate of discontinuations caused by AEs. [ABSTRACT FROM AUTHOR]

For the quantitation of most drugs and their metabolites, GC-MS is currently the preferred method and isotopically labeled analogs of the analytes are the internal standards (ISs) of choice. Under this analytical setting, chemical derivatization (CD) plays a critical role in the sample preparation process. In addition to meeting the conventional objectives of CD, products derived from the selected CD method must generate ions suitable for designating the analyte and the IS; these ions cannot have significant cross-contribution (CC), i.e., contribution to the intensity of the ions designating the analyte by the IS, and vice versa. With this in mind, the authors have reviewed literature and information provided by manufacturers, searching for suitable CD reagents, CD methods, and isotopically labeled analogs of the analytes related to the following 11 opioids: heroin, 6-acetylmorphine, morphine, hydromorphone, oxymorphone, 6-acetylcodeine, codeine, hydrocodone, dihydrocodeine, oxycodone, and noroxycodone. These analytes and ISs were derivatized with various derivatization groups, followed by GC-MS analysis. The resulting MS data are systematically presented in two forms: (a) full-scan mass spectra; and (b) CC data of ion-pairs with potential for designating the analytes and their respective ISs. Many (if not most) of these full-scan mass spectra are not yet available in the literature and should be of reference value to laboratories engaged in the analysis of these drugs/metabolites. Full-scan MS data were further used to select ion-pairs with potential for designating the analytes and ISs in quantitative analysis protocols. The CC data of these ion-pairs were evaluated using data collected in selected ion monitoring mode and systematically tabulated, readily available for analysts searching for this important analytical parameter. [ABSTRACT FROM AUTHOR]

Objective To determine if oxymorphone and hydromorphone are equally efficacious as analgesics in both dogs and cats and to determine the side-effects of each drug in painful animals. Study design Randomized, blinded, clinical trial. Animals 151 animals (28 cats and 123 dogs) admitted to the intensive care unit requiring μ opioid agonist treatment for a variety of painful procedures. Methods Animals were randomized into two groups and received either hydromorphone or oxymorphone as their primary μ agonist agent. All staff and clinicians were blinded as to which drug was administered. Pain scores, side-effects, dose and duration were recorded for each drug dose administered. The study groups were not revealed until the study had been completed and the ensuing manuscript written. Implementation of reversal and rescue protocols were dependent on pain scores and the judgment of the primary clinician. Results The groups did not significantly differ at randomization or in the number of study drug doses. There were no statistical differences between the dose of drug or the time between each dose, indicating that potency and efficacy was not different between the two drugs. Significantly more animals that received hydromorphone vomited, but there were no other statistical differences in adverse events, or in requirement for rescue or reversal protocols. Conclusions and Clinical relevance Hydromorphone is significantly less expensive than oxymorphone and the results of this trial indicate that the two drugs have a similar clinical value. Both oxymorphone and hydromorphone can be used as primary μ agonist therapy in veterinary patients. [ABSTRACT FROM AUTHOR]

Chronic pain is a condition affecting a vast patient population and resulting in billions of dollars in associated health care costs annually. Sufferers from severe chronic pain often requite twenty-four hour drug treatment through intrusive means and/or repeated oral dosing. Although the oral route of administration is most preferred, conventional immediate release oral dosage forms lead to inconvenient and suboptimal drug therapies for the treatment of chronic pain. Effective drug therapies for the management of chronic pain therefore require advanced formulation design to optimize the delivery of potent analgesic agents. Ideally, these advanced delivery systems provide efficacious pain therapy with minimal side effects via a simple and convenient dosing regime. In this article, currently commercialized and developing drug products for pain management are reviewed with respect to dosage form design as well as clinical efficacy. The drug delivery systems reviewed herein represent advanced formulation designs that are substantially improving analgesic drug therapies. [ABSTRACT FROM AUTHOR]

Abstract: Opioids are extensively used analgesics yet can paradoxically increase pain sensitivity in humans and rodents. This hyperalgesia is extensively conceptualized to be a consequence of opioid receptor activity, perhaps providing an adaptive response to analgesia, and to utilize N-methyl-d-aspartate (NMDA) receptors. These assumptions were tested here in opioid receptor triple knock-out (KO) mice lacking all three genes encoding opioid receptors (μ, δ, and κ) by comparing their thermal nociceptive responses to the opioids morphine and oxymorphone with those of B6129F1 controls. Injecting acute opioid bolus doses in controls caused maximal analgesia that was completely abolished in KO mice, confirming the functional consequence of the KO mouse opioid receptor deficiency. Continuous opioid infusion by osmotic pump in control mice also initially caused several consecutive days of analgesia that was shortly thereafter followed by several consecutive days of hyperalgesia. In contrast, continuously infusing KO mice with opioids caused no detectable analgesic response, but only immediate and steady declines in nociceptive thresholds culminating in several days of unremitting hyperalgesia. Finally, injecting the non-competitive NMDA receptor antagonist MK-801 during opioid infusion markedly reversed hyperalgesia in control but not KO mice. These data demonstrate that sustained morphine and oxymorphone delivery causes hyperalgesia independently of prior or concurrent opioid or NMDA receptor activity or opioid analgesia, indicating the contribution of mechanisms outside of current conceptions, and are inconsistent with proposals of hyperalgesia as a causative factor of opioid analgesic tolerance. [Copyright &y& Elsevier]

Abstract Background:: Patients are typically switched from parenteral opioids to oral opioids during the 24 to 48 hours after surgery. In June 2006, an oral immediate-release (IR) tablet formulation of oxymorphone was approved for the treatment of acute moderate to severe pain. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery. Objective:: This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery. Methods:: This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women aged ≥18 years undergoing abdominal surgery that required a ≥3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity ≥50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15-minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). Results:: Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment-emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. Conclusion:: In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain. [Copyright &y& Elsevier]

Abstract: A method was developed for quantification of oxycodone, noroxycodone, and oxymorphone in small volumes (50μl) of rat plasma by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry using turbo ion-spray. Deuterated (d3) opioid analogues acted as internal standards. Sample preparation involved protein precipitation with acetonitrile, centrifugal evaporation, and reconstitution in mobile phase; analyte separation was performed on a C18 (5μm, 2.1mm×50mm) column using a linear gradient program. Lower limits of quantitation (ng/ml) and their between-day accuracy and precision were—oxycodone, 0.9 (−0.2 and 7.8%); noroxycodone, 1.0 (0.6 and 6.2%); oxymorphone 1.0 (−1.8 and 9.5%). [Copyright &y& Elsevier]

Abstract: Opioid-experienced (N = 250) patients with chronic, moderate to severe low back pain (LBP) were converted from their prestudy opioid(s) to an approximately equianalgesic dose of OPANA ⁎ ER (oxymorphone extended release). Patients continued slow titration, with 56% stabilized within 1 month to a dose of OPANA ER that reduced average pain to <40 mm on a visual analog scale with good tolerability. Stabilized patients (n = 143) were randomized to placebo or their stabilized dose of OPANA ER every 12 hours for a 12-week double-blind period. Pain intensity increased significantly more for patients randomized to placebo than for patients who continued their stabilized dose of OPANA ER; the increase from baseline (at randomization) to final visit was 31.6 mm for placebo versus 8.7 mm with OPANA ER (P < .0001). During double-blind treatment, placebo patients were approximately 8-fold more likely than OPANA ER patients to discontinue because of lack of efficacy (P < .001). Discontinuations as a result of adverse events were similar between groups, 10% with placebo and 11% with OPANA ER. Opioid-related adverse events included constipation (6%), somnolence (3%), and nausea (3%). Fifty-seven percent of opioid-experienced patients with chronic, moderate to severe LBP achieved a stable dose of OPANA ER that was efficacious and generally well-tolerated for up to 12 weeks. Perspective: In a 12-week, double-blind, randomized, placebo-controlled trial in opioid-experienced patients with chronic, moderate to severe LBP, OPANA ER provided efficacious, long-term analgesia and was generally well-tolerated. OPANA ER may provide clinicians with a new treatment option for patients experiencing suboptimal analgesic responses or poor tolerability with other opioids. [⁎] OPANA is a registered trademark of Endo Pharmaceuticals, Chadds Ford, PA. [Copyright &y& Elsevier]

Abstract: Background:: Oxymorphone extended release (ER) is a tablet formulation of the μ-opioid agonist oxymorphone designed to achieve a low peak-to-trough fluctuation in plasma concentrations over a 12-hour dosing period. Objective:: This study compared the analgesic efficacy, dose response, and tolerability of 3 doses of oxymorphone ER given every 12 hours with those of placebo in patients with pain related to osteoarthritis (OA) of the hip or knee. Methods:: This was a 2-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, Phase III trial. Patients with OA of the hip or knee who were receiving an opioid medication for chronic, moderate to severe pain or who were judged by the investigator to have received suboptimal analgesia with nonopioid analgesics entered a 2- to 7-day washout of analgesic medication. When pain in the index joint was >40 mm on a 100-mm visual analog scale (VAS), patients were randomized to receive 1 of 4 regimens: oxymorphone ER 10 mg q12h during weeks 1 and 2; oxymorphone ER 20 mg q12h in week 1 and 40 mg q12h in week 2; oxymorphone ER 20 mg q12h in week 1 and 50 mg q12h in week 2; or placebo q12h during weeks 1 and 2. The primary end point was the change in VAS score for arthritis pain intensity. Other assessments included the Western Ontario and McMaster Universities (WOMAC) OA Index subscales for pain, stiffness, and physical function and the composite index; the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical health component summary (PCS) score; the Chronic Pain Sleep Inventory (CPSI) score; vital signs; clinical laboratory parameters; and adverse events (AEs). AEs were recorded at each clinic visit. Results:: Three hundred seventy patients were randomizedto treatment (95 oxymorphone ER 10 mg, 93 oxymorphone ER 40 mg, 91 oxymorphone ER 50 mg, and 91 placebo), and 198 completed the study. Least squares mean changes from baseline in the VAS arthritis pain intensity score were −21, −28, −29, and −17 mm in the oxymorphone ER 10, 40, and 50 mg and placebo groups, respectively (P = 0.002, modified Tukey linear trend test). Oxymorphone ER 40 and 50 mg produced significant improvements from baseline compared with placebo in the WOMAC subscale scores for pain (least squares mean change: −85.1, −108.0, and −42.5, respectively; P ≤ 0.025 for 40 mg, P ≤ 0.001 for 50 mg), stiffness (−40.5, −48.1, and −17.0; both, P ≤ 0.001), and physical function (−256.8, −310.8, and −116.5; P ≤ 0.01 and P ≤ 0.001, respectively); the SF-36 PCS score (4.6, 3.6, and −0.1; P < 0.001); and the CPSI score (−21.2, −22.2, and −10.7; P < 0.05). The 10-mg dose also was associated with significant improvements compared with placebo in the WOMAC pain (−83.6; P ≤ 0.025) and physical function subscales (−232.9; P ≤ 0.025) and the SF-36 PCS score (3.9; P < 0.001). The most frequently reported AEs (≥5% of patients) in the oxymorphone ER groups were nausea (39.4%), vomiting (23.7%), dizziness (22.6%), constipation (22.2%), somnolence (17.6%), pruritus (16.5%), and headache (15.0%). The majority of AEs with oxymorphone ER were mild or moderate in intensity. Three serious AEs (urinary retention, central nervous system depression, and pancreatitis) were considered possibly or probably related to study medication. Conclusion:: In these patients with chronic, moderate to severe pain related to OA of the hip or knee, oxymorphone ER administered twice daily for 2 weeks produced dose-related reductions in arthritis pain intensity and improvements in physical function. [Copyright &y& Elsevier]

Objectives To quantify the change in the minimum alveolar concentration (MAC) of isoflurane (ISO) associated with oxymorphone (OXY) or hydromorphone (HYDRO) in dogs. Design Randomized crossover study with at least 1 week between assessments. Animals Six young, healthy, mixed-breed dogs (1–3 years old), weighing 24.7 ± 4.70 kg. Methods Following mask induction, anesthesia was maintained with ISO in 100% O2 using mechanical ventilation. The dogs received 0.05 mg kg−1 OXY, 0.1 mg kg−1 HYDRO, or 1 mL saline (control) IV. Following equilibration (15 minutes) at each percentage ISO tested, a supramaximal electrical stimulus was applied to the toe web and the response was assessed. Two separate MAC determinations were carried out during 4.5 hours of anesthesia, with completion of the evaluations at 1.5–2 and 4–4.5 hours after drug administration. A two-factoranova was used to determine whether there was a time or treatment effect on MAC and a Tukey test compared the drug effects at each time. Significance is reported at p < 0.05. Results The mean MAC values (±SD) were 1.2 ± 0.18 and 1.2 ± 0.16% for control, 0.7 ±0.15 and 1.0 ± 0.15% for OXY, and 0.6 ± 0.14 and 0.8 ± 0.17% for HYDRO. The initial MAC with OXY and the MAC determined at both times with HYDRO were significantly different from the control MAC values. Conclusions Both OXY and HYDRO significantly reduced the MAC of ISO in dogs at 2 hours. At approximately 4.5 hours, HYDRO had a significant MAC-sparing effect, whereas OXY did not. Clinical relevance Although both OXY and HYDRO resulted in a significant reduction in the MAC of ISO at approximately 2 hours, HYDRO may be preferred for procedures of long duration and rarely needs repeated dosing before 4.5 hours. [ABSTRACT FROM AUTHOR]