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Background: Opioids provide effective pain control, yet have risks including adverse events (AEs) (e.g., constipation, nausea/vomiting, sedation) and cognitive/psychomotor effects. Objective: To compare cognitive and psychomotor effects of oxymorphone extended release (OM-ER) versus oxycodone controlled release (OC-CR). Study design: Randomized, double-blind, 5-way crossover Setting: Single inpatient research unit Methods: Nondependent recreational opioid users were administered single intact oral tablets of placebo, OM-ER (15 and 30 mg), and OC-CR (30 and 60 mg), separated by a 7- to 21-day washout. The divided attention (DA) test measured psychomotor impairment (e.g., manual tracking [e.g., percentage over road], target accuracy [e.g., target hits], reaction time [hit latency]). Visual analog scales measured alertness/drowsiness, agitation/relaxation, and dizziness. Sedative, stimulant, and dysphoric effects were measured using the Addiction Research Center Inventory PentobarbitalChlorpromazine-Alcohol (PCAG), Benzedrine Group (BG), and Lysergic Acid Diethylamide (LSD) scales, respectively. Comparisons were made between equianalgesic doses (OM-ER 15 mg vs OCCR 30 mg; OM-ER 30 mg vs OC-CR 60 mg), within active drug doses, and between active drugs and placebo using least squares (LS) mean difference of the peak maximum (Emax) or minimum (Emin) effect using linear mixed model analysis of covariance. Results: Thirty-five participants received all 5 treatments. Peak cognitive and psychomotor impairment (LS mean [SE]) was less with OM-ER than equianalgesic doses of OC-CR for reaction time (Emax hit latency, longer if impaired; 571.2 [13.4] vs 588.1 ms [13.4], P=0.03 for OM-ER 15 mg vs OC-CR 30 mg, respectively; 572.4 [13.4] vs 604.3 ms [13.4], P

OBJECTIVE: To review the chemistry, pharmacodynamics, pharmacokinetics, efficacy, tolerability, dosing, and role of the Osmotic-controlled Release Oral delivery System (OROS) hydromorphone extended-release (ER) tablets. DATA SOURCE: A MEDLINE/PUBMED search (1986-August 2010) was conducted to identify studies in the English language, with additional references being obtained from their bibliographies. STUDY SELECTION: All studies of hydromorphone ER were reviewed. DATA SYNTHESIS: This is the second long-acting hydromorphone formulation to receive approval by the Food and Drug Administration (a twice-daily formulation was approved in September 2004, but was subsequently withdrawn in July 2005). Hydromorphone is a semi-synthetic mu-opioid receptor agonist structurally similar to morphine, hydrocodone, and oxymorphone. OROS ER technology allows once-daily dosing. Clinical trials have focused on the convertibility of (an) other opioid(s) to hydromorphone ER in chronic malignant and nonmalignant pain. This product displays the expected opioid side effects, being comparable to oxycodone controlled-release. Coadministration with ethanol does not produce the degree of "dose-dumping" seen with the former hydromorphone twice-daily product or oxymorphone ER. Hydromorphone ER is indicated for the management of moderate-to-severe pain in opioidtolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time. Dosage adjustment is recommended in patients with moderate hepatic impairment (Child-Pugh class B) and moderate renal impairment (creatinine clearance of 30-60 mL/min). CONCLUSION: Hydromorphone ER is the newest oral opioid to enter a crowded marketplace now totaling 15 different Schedule 2 opioids (including tapentadol), and tramadol, available in oral, parenteral, rectal, transdermal, transmucosal, and intranasal formulations. It does not appear to have any unique assets or liabilities and should be considered as one of many oral opioids available for the management of persistent pain of moderate-to-severe intensity.

Two cases are reported involving the abuse of extended-release oxymorphone hydrochloride tablets (Opana® ER) in combination with alprazolam (Xanax®). Two juvenile females were discovered unresponsive and hypoxic by a male acquaintance. The trio had reportedly crushed and snorted Opana ER tablets and consumed Xanax for recreational purposes. Emergency personnel were able to stabilize one female. The second female was pronounced dead at the scene. Blood and urine samples from the surviving female were collected at the trauma center between 48 and 96 h post incident. Toxicology results showed the presence of oxymorphone, doxylamine, dextromethorphan, alprazolam, α-hydroxyalprazolam, oxazepam, and temazepam in her urine. No drugs were detected in her blood. Toxicology on the deceased female revealed the presence of 0.13 mg/L oxymorphone and 0.04 mg/L alprazolam in her blood. Gastric contents contained 0.25 and 0.93 mg/L of oxymorphone and alprazolam, respectively. Oxymorphone, alprazolam, and α-hydroxyalprazolam were present in her urine. Quantitative results were achieved by gas chromatography-mass spectrometry monitoring selected ions for the oxime-oxymorphone-trimethylsilyl derivative, alprazolam, and the α-hydroxyalprazolam tert-butyldimethylsilyl derivative. The established linearity ranges for the opiate and benzodiazepine methods were 0.050-3.000 and 0.025-1.000 mg/L, respectively. The cause of death was reported as multiple drug toxicity, and the manner of death was accidental.

Grapefruit juice alters the concentrations of many CYP3A substrates. The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞) ) by 1.7-fold (p

Objective. To examine the development of analgesic tolerance in patients on oxymorphone extended-release (OxymER). Design. Post hoc analysis of data from a previously conducted prospective 1 year multi-center open-label extension study in which patients were able to titrate as needed. Patients. Sample of 153 hip and knee osteoarthritis (OA) subjects on OxymER. Primary analyses were limited to study completers (n = 62) due to the large amount of missing data for the noncompleters (n = 91). Outcome Measures. Main outcome measures included OxymER doses (pill counts) and pain intensity ratings using a visual analog scale at monthly visits. Results. There were significant dose increases from weeks 1 to 2 and 2 to 6 (P

BACKGROUND AND PURPOSE: There is high interindividual variability in the activity of drug-metabolizing enzymes catalysing the oxidation of oxycodone [cytochrome P450 (CYP) 2D6 and 3A], due to genetic polymorphisms and/or drug-drug interactions. The effects of CYP2D6 and/or CYP3A activity modulation on the pharmacokinetics of oxycodone remains poorly explored. EXPERIMENTAL APPROACH: A randomized crossover double-blind placebo-controlled study was performed with 10 healthy volunteers genotyped for CYP2D6 [six extensive (EM), two deficient (PM/IM) and two ultrarapid metabolizers (UM)]. The volunteers randomly received on five different occasions: oxycodone 0.2 mg x kg(-1) and placebo; oxycodone and quinidine (CYP2D6 inhibitor); oxycodone and ketoconazole (CYP3A inhibitor); oxycodone and quinidine+ketoconazole; placebo. Blood samples for plasma concentrations of oxycodone and metabolites (oxymorphone, noroxycodone and noroxymorphone) were collected for 24 h after dosing. Phenotyping for CYP2D6 (with dextromethorphan) and CYP3A (with midazolam) were assessed at each session. KEY RESULTS: CYP2D6 activity was correlated with oxymorphone and noroxymorphone AUCs and C(max) (-0.71 < Spearman correlation coefficient rhos < -0.92). Oxymorphone C(max) was 62% and 75% lower in PM than EM and UM. Noroxymorphone C(max) reduction was even more pronounced (90%). In UM, oxymorphone and noroxymorphone concentrations increased whereas noroxycodone exposure was halved. Blocking CYP2D6 (with quinidine) reduced oxymorphone and noroxymorphone C(max) by 40% and 80%, and increased noroxycodone AUC(infinity) by 70%. Blocking CYP3A4 (with ketoconazole) tripled oxymorphone AUC(infinity) and reduced noroxycodone and noroxymorphone AUCs by 80%. Shunting to CYP2D6 pathway was observed after CYP3A4 inhibition. CONCLUSIONS AND IMPLICATIONS: Drug-drug interactions via CYP2D6 and CYP3A affected oxycodone pharmacokinetics and its magnitude depended on CYP2D6 genotype.

Urine drug testing of pain patients provides objective information to health specialists regarding patient compliance, diversion, and concurrent illicit drug use. Interpretation of urine test results for semi-synthetic opiates can be difficult because of complex biotransformations of parent drug to metabolites that are also available commercially and may be abused. Normetabolites such as norcodeine, norhydrocodone and noroxycodone are unique metabolites that are not available commercially. Consequently, detection of normetabolite in specimens not containing parent drug, provides conclusive evidence that the parent drug was consumed. The goal of this study was to evaluate the prevalence and patterns of the three normetabolites, norcodeine, norhydrocodone and noroxycodone, in urine specimens of pain patients treated with opiates. Urine specimens were hydrolyzed with beta-glucuronidase and analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) assay for the presence of codeine, norcodeine, morphine, hydrocodone, norhydrocodone, hydromorphone, dihydrocodeine, oxycodone, noroxycodone, and oxymorphone. The limit of quantitation (LOQ) for these analytes was 50ng/mL. The study was approved by an Institutional Review Board. Of the total specimens (N=2654) tested, 71.4% (N=1895) were positive (>or=LOQ) for one or more of the analytes. The prevalence (%) of positive results for codeine, hydrocodone and oxycodone was 1.2%, 26.1%, and 36.2%, respectively, and the prevalence of norcodeine, norhydrocodone and noroxycodone was 0.5%, 22.1%, and 31.3%, respectively. For specimens containing normetabolite, the prevalence of norcodeine, norhydrocodone and noroxycodone in the absence of parent drug was 8.6%, 7.8% and 9.4%, respectively. From one-third to two-thirds of these specimens also did not contain other metabolites that could have originated from the parent drug. Consequently, the authors conclude that inclusion of norcodeine, norhydrocodone and noroxycodone is useful in interpretation of opiate drug source and reduces potential false negatives that would occur without tests for these unique metabolites.

The addictive potential of opioids may be related to their differential ability to induce G protein signaling and endocytosis. We compared the ability of 20 ligands (sampled from the main chemical classes of opioids) to promote the association of mu and delta receptors with G protein or beta-arrestin 2. Receptor-arrestin binding was monitored by bioluminescence resonance energy transfer (BRET) in intact cells, where pertussis toxin experiments indicated that the interaction was minimally affected by receptor signaling. To assess receptor-G protein coupling without competition from arrestins, we employed a cell-free BRET assay using membranes isolated from cells expressing luminescent receptors and fluorescent Gbeta(1). In this system, the agonist-induced enhancement of BRET (indicating shortening of distance between the two proteins) was G alpha-mediated (as shown by sensitivity to pertussis toxin and guanine nucleotides) and yielded data consistent with the known pharmacology of the ligands. We found marked differences of efficacy for G protein and arrestin, with a pattern suggesting more restrictive structural requirements for arrestin efficacy. The analysis of such differences identified a subset of structures showing a marked discrepancy between efficacies for G protein and arrestin. Addictive opiates like morphine and oxymorphone exhibited large differences both at delta and mu receptors. Thus, they were effective agonists for G protein coupling but acted as competitive enkephalins antagonists (delta) or partial agonists (mu) for arrestin. This arrestin-selective antagonism resulted in inhibition of short and long term events mediated by arrestin, such as rapid receptor internalization and down-regulation.

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

Oxycodone is a semisynthetic opioid analgesic largely prescribed for post-operative and chronic pain management. The introduction of a slow release formulation of oxycodone has led to its frequent abuse and to an increase in emergency cases related to oxycodone overdose. Until recently, oxycodone testing has been confined to gas chromatography-mass spectrometry (GC-MS) analysis because the widely used automated opiate immunoassays poorly react to this compound. We investigated the utility of a new oxycodone immunoassay as a screening procedure to eliminate inappropriate GC-MS testing of negative urine specimens. We analyzed 96 urine specimens using GC-MS and two immunoassays, CEDIA((R)) opiates and DRI((R)) oxycodone assays from Microgenics, on a Hitachi 917 analyzer. The GC-MS allowed us to detect codeine, hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone following enzymatic hydrolysis and derivation by acetylation. The combination of the two immunoassays gave the best performance (98% sensitivity and specificity) when considering a positive result from GC-MS for any of the opiates. Considering positive GC-MS results for oxycodone or oxymorphone only, the oxycodone immunoassay resulted in two false-positives and one false-negative (50 ng/mL cutoff). Using these immunoassays for screening before GC-MS analysis provides a reduced opiate GC-MS workload without compromising quality.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. • So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied. WHAT THIS STUDY ADDS • Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone. • When both of CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially. AIM The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone. METHODS A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated. RESULTS Paroxetine alone reduced the area under concentration–time curve (AUC(0,0–48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,∞) of oxycodone increased by 2.9-fold (P < 0.001), and its Cmax by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo. CONCLUSIONS Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.

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 (20 mg/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 AUC0–12 h 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.

There has been an increased awareness of illicit opiate abusers using the narcotic oxymorphone (Opana) by inhalation. Many laboratory screening techniques currently in use cannot detect oxymorphone in blood or urine. Consequently, biological specimens containing low to moderate concentrations of oxymorphone will likely go undetected. The circumstances, pathology findings, and toxicology results of two fatalities involving oxymorphone are presented. An opiate confirmation gas chromatography-mass spectrometry (GC-MS) procedure, described in detail was able to detected, confirm, and quantify oxymorphone in both subjects. The blood concentrations were 0.05 mg/L (50 microg/L) and 0.12 mg/L (120 microg/L).

A series of new 14-hydroxymorphinan analogues with a thiazole or imidazo[2,1-b]thiazole fragment as the heterocyclic function fused to ring C were designed and synthesized. These compounds can be viewed as the result of a direct modification at ring C of the 14-hydroxymorphinan scaffold. Among these compounds, three were identified as having potent binding affinity (approximately 1 nM) at both kappa and mu receptors, and acting as agonists at kappa and partial agonists or antagonists at mu receptors. In view of the promising results from studies on compounds with mixed kappa and mu receptor activities, these new compounds warrant further investigation.

The intent of this study was to review fatalities involving oxycodone in the west of Scotland using a liquid chromatography-electrospray ionization-tandem mass spectrometry method developed for the determination of oxycodone and N- and O-demethylated metabolites in unhydrolyzed postmortem specimens. Ten oxycodone positive postmortem cases were detected, and nine were drug-related fatalities. Five cases were attributed solely to oxycodone intoxication and four to polydrug intoxication. Although there was overlap between blood oxycodone levels in deaths attributed to oxycodone only and those due to polydrug intoxication, lower oxycodone levels (1 mg/L) were associated with polydrug intoxication when compared with cases due to oxycodone alone (1 mg/L). The role of the parent drug in oxycodone fatalities has been fully studied, but the role of oxycodone metabolites (noroxycodone and oxymorphone) was investigated in this report for the first time. Oxycodone was more commonly detected in blood, urine, and vitreous humor followed by noroxycodone. The ratio between oxycodone and its N-demethylated metabolite was evaluated and found to be useful in determining whether death occurred shortly after drug administration or if there was a significant delay. High parent/metabolite ratios were correlated with short survival times after ingestion. The median ratio of oxycodone/noroxycodone was 2.4 and ranged from 0.7 to 49. Oxycodone prescriptions have risen sharply in Scotland in recent years, and the identification of 10 oxycodone-related deaths in the past 18 months highlights the importance of including this drug in routine laboratory screening and confirmation procedures.

Pain among the elderly is pervasive, under-treated and can be properly managed by judiciously using analgesics in the armamentarium. For severe pain, opioids generally provide the most effective pain relief, but concerns about safety and tolerability have limited, often unnecessarily, their utilization in the geriatric population.It is common for geriatric patients to be taking more than one medicine. Oxymorphone might be particularly well suited for use in geriatric patients, in that its metabolism is mainly through non-CYPP450 pathways, thereby posing less risk of interaction with the many drugs that are metabolized by the CYPP450 system. However, oxymorphone is not as familiar to clinicians as morphine or some other opioids. We review here the clinical studies on oxymorphone to outline the key considerations for use of oxymorphone in the geriatric population.Nine available clinical trials of oxymorphone alone or comparing oxymorphone with placebo or other active agents were analyzed with respect to the safety and tolerability findings. These studies included geriatric patients but were not designed to evaluate oxymorphone exclusively in this population.Based on the results from nine published clinical studies, oxymorphone is an effective opioid analgesic with a safety profile at least comparable to other opioid drugs. At low starting doses and individual titration, oxymorphone should be considered for appropriate geriatric patients, particularly in whom there is concern about interaction with drugs that are metabolized by CYPP450 enzymes.

Background Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. Methods The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. Results Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated. Conclusions Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

Internal standards (IS) with similar physicochemical properties to the analyte provide multiple advantages in liquid chromatography/tandem mass spectrometric (LC/MS/MS) bioanalytical methods such as: reduction of the analysis run time, improvement in the intra-injection reproducibility, impact reduction of matrix and ionization effects. However, it is important to evaluate the purity of the IS prior to their use. Indeed, a minor impurity in the IS may lead to an important issue during bioanalytical method development. Stable labelled internal standards are usually appropriate IS for bioanalysis. The use of oxycodone-D3, ursodiol-D5 and atovaquone-D4 as internal standards in three different bioanalytical methods was evaluated. During oxycodone, oxymorphone and noroxycodone simultaneous quantification method development, oxymorphone was identified as a contaminant in oxycodone-D3. Since the limit of quantification for oxymorphone was very low (10 pg/mL), the presence of an even low percentage of oxymorphone in oxycodone-D3 leads to the change of the stable labelled IS for an analogue, ethylmorphine. 23-Nordeoxycholic acid was preferred to ursodiol-D5 as internal standard for the ursodiol, tauroursodiol and glycoursodiol simultaneous quantification method. Indeed, more than 7% of ursodiol was identified in the ursodiol-D5 which could not be bypassed by decreasing the IS concentration without compromising the linearity. An atovaquone-D4 reference standard revealed the non-negligible presence of atovaquone-D5 to atovaquone-D8 that has a large impact on the method validation. Therefore, atovaquone-D4 was sent for recertification since its isotopic purity was found to be much less than the isotopic purity mentioned on its certificate of analysis. Consequently, during bioanalytical method development, the purity of the IS should be scrutinized.

As morphine, oxycodone is a m-opioid receptor agonist with a significantly different pharmacokinetic profile compared with morphine. It seems that oxycodone is able to compensate its lower binding affinity for the m-opioid receptor compared with that of morphine by active transport to the central nervous system. Although the analgesic properties of oxycodone are mainly due to its own activity, cytochrome (CYP) inhibitors and inductors may change oxycodone-induced analgesia as a result of higher or lower, respectively, oxycodone concentrations.

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 mu-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 (6alpha- and 6beta-oxymorphols) found to be similar for mu-opioid receptor binding affinity (K(d) = 15 versus 14 nM) and calcium activation (EC(50) = 22 versus 14 nM). Calcium activation was then inhibited in CHO cells in a concentration-dependent manner using the irreversible mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA). Under these conditions, approximately 10-fold greater receptor reserve was found for 6alpha-oxymorphol compared to 6beta-oxymorphol. This difference between the oxymorphols corresponded to a rank order of intrinsic efficacy (Emax): DAMGO > oxymorphone = 6alpha-oxymorphol = oxycodone > 6beta-oxymorphol. In addition, 6alpha-oxymorphol exhibited greater relative potency than the 6beta-oxymorphol in mouse tail-flick, hot-plate and phenylquinone writhing antinociceptive assays, regardless of route of administration. Thus the beta-FNA/calcium model provides a novel, cell-based approach to distinguish structurally related mu-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.

The objectives of the study were to determine the pharmacokinetics of oxymorphone (oxy) and of ammonium sulfate-loaded, liposome-encapsulated oxymorphone (LE-ASG oxy) and to evaluate the behavioral effects of both opioid preparations by using ethographic evaluation specific to rhesus monkeys. Rhesus monkeys (n = 8) were injected with 2.0 mg/kg LE-ASG oxy s.c.. Blood samples were collected at serial time points up to 144 h in six monkeys and up to 456 h in two monkeys. Separate groups of monkeys were injected with 0.1 mg/kg oxy s.c. (n = 4) or i.v. (n = 5). Blood samples were collected at serial time points up to 24 h after injection. Pharmacokinetic parameters were calculated by using commercially available software. Behavior was recorded in a different group of 10 monkeys administered LE-ASG oxy (2.0 mg/kg s.c.) or oxy (0.1 mg/kg s.c.) on separate occasions. Behavioral evaluations were made at serial time points while monkeys were in an extended cage with a compatible stimulus animal. Oxymorphone was rapidly eliminated from the serum in the oxy group. Measurable drug was present in serum for up to 4 h after oxy was administered subcutaneously or intravenously. LE-ASG oxy was present in serum in measurable concentrations for more than 2 weeks. Neither oxy nor LE-ASG oxy produced observable sedation. LE-ASG oxy decreased some environmentally directed behaviors, but this drug formulation increased watchfulness, decreased self-directed and elimination behaviors, increased nonspecific social contact, and decreased threat behaviors. LE-ASG oxy persisted for an extended period in rhesus monkey serum and produced behavioral changes consistent with this opioid.

Udgivelsesdato: 2009-Apr Oxycodone is O-demethylated by CYP2D6 to oxymorphone which is a potent micro-receptor agonist. The CYP2D6 oxidation polymorphism divides the Caucasian population in two phenotypes: approximately 8% with no enzyme activity, poor metabolizers (PM) and the remainder with preserved CYP2D6 activity, extensive metabolizers (EM). The objective of the study was to determine if the analgesic effect of oxycodone in human experimental pain depends on its metabolism to oxymorphone. The analgesic effect of oxycodone was evaluated in a randomized, placebo-controlled, double-blinded, crossover experiment including 33 (16 EM and 17 PM) healthy volunteers. Pain tests were performed before and 1, 2, 3 and 4 hr after medication and included pain detection and tolerance thresholds to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation and the cold pressor test with rating of discomfort and pain-time area under curve (AUC(0-2 min.)). For single sural nerve stimulation, there was a less pronounced increase in thresholds on oxycodone in pain detection (9% vs. 20%, P = 0.02, a difference of 11%, CI: 2%-20%) and pain tolerance thresholds (15% vs. 26%, P = 0.037, a difference of 10%, CI: 1%-20%) for PM compared with EM. In the cold pressor test, there was less reduction in pain AUC on oxycodone for PM compared with EM (14% vs. 26%, P = 0.012, a difference of 12%, CI: 3%-22%). The plasma oxymorphone/oxycodone ratio was significantly lower in PM compared with EM (P < 0.001). Oxycodone analgesia seems to depend both on oxycodone itself and its metabolite oxymorphone.

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.

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.

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.

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-naive) 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.

Over the past 10–20 years researchers have enhanced our understanding of the metabolism and risk of drug interactions of numerous medications utilized by patients with pain conditions. Pain patients often are prescribed multiple medications that can inhibit or induce specific cytochrome P450 (CYP450) enzymes. This review will focus on the effect of the CYP450 enzyme system metabolism on opioid agents codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone, as well as the potential effect of these opioids on the metabolism of other medications and vice versa.

A hypothesis on reciprocal interactions between the central and peripheral components of the endogenous opioid system was formulated on the basis of results of our experimental studies and published data. In order to verify this hypothesis, we studied the effects of peripheral administration of loperamide (mu-opioid receptor agonist) and methylnaloxone (opioid receptor antagonist) not penetrating through the blood-brain barrier on the pain sensitivity of rats, morphine-induced analgesia, and formation of morphine analgesia tolerance. Peripheral loperamide and methylnaloxone modulated the central mechanisms of perception of painful stimuli. This fact confirmed the hypothesis on the reciprocal interactions between the central and peripheral compartments of the endogenous opioid system. Methylnaloxone exhibits an antagonistic effect on peripheral mu-opioid receptors, which probably leads to activation of the central mu-opioid receptors and to the development of analgesia. Loperamide activates peripheral, but suppresses the central mu-opioid receptors, which leads to hyperalgesia. Methylnaloxone suppresses morphine-induced analgesia under conditions of morphine activation of the central antinociceptive mechanisms. Peripheral injection of mu-opioid agonist loperamide virtually did not modify the central compartments of the opioid system under conditions of morphine treatment. Methylnaloxone and loperamide partially prevented the development of morphine analgesia tolerance. Hence, the results confirm the hypothesis about the reciprocal interactions between the central and peripheral compartments of the endogenous opioid system. The relationships between the central and peripheral compartments of the opioid system can be more intricate when its function is modulated.

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.

We have noticed increased prescribing of tramadol by emergency physicians for breakthrough pain in patients chronically taking oxycodone. Both oxycodone and tramadol undergo oxidative metabolism by CYP2D6 and CYP3A4, suggesting the possibility that tramadol may compete with oxycodone for metabolism. A randomized controlled trial in 10 human volunteers was performed to determine if single-dose tramadol therapy would impair oxycodone clearance. Subjects were randomized whether to enter the control or experimental arm of the study first, with each subject serving as his or her own control. In the control arm, each subject received 10 mg immediate-release oxycodone orally and had serial plasma oxycodone and oxymorphone concentrations measured over 8 h. The experimental arm was identical except that 100 mg tramadol was ingested 1.5 h before oxycodone. Clearance divided by fraction absorbed (CL/f) was calculated using the dose and the area under the 8-h time-plasma oxycodone concentration curve. Peak plasma oxycodone concentrations (C(max)) and time until peak oxycodone concentrations (T(max)) were secondary outcome parameters. Group size was chosen to produce a power of 0.8 to detect a 20% difference in CL/f between study arms. Values for CL/f, C(max), and T(max) were compared between study arms using two-tailed, paired t-tests. No statistically significant difference between groups was demonstrated for any parameter. We failed to demonstrate that single doses of tramadol impaired oxycodone clearance.

Human urine specimens that were determined to be presumptively positive for oxycodone and its metabolite, oxymorphone, by immunoassay screening were assayed using fast gas chromatography-mass spectrometry to positively identify and quantify the oxycodone and oxymorphone present. Urine specimens were first spiked with deuterated internal standards, oxycodone-d(3) and oxymorphone-d(3), subjected to acid hydrolysis, and then extracted using a positive-pressure manifold and mixed-bed solid-phase cartridge extraction methodology. Extracts were derivatized using methoxylamine and acetic anhydride. The acetylated-oxime derivatives of oxycodone and oxymorphone were identified and quantified using a selective ion monitoring (SIM). The method was found to be linear for both analytes to 1600 ng/mL, and limits of detection for oxycodone and oxymorphone were found to be 40 ng/mL and 20 ng/mL, respectively. Interlaboratory data comparisons (n = 40) showed correlation coefficients of 0.9999 and 0.9997 for oxycodone and oxymorphone, respectively. Twelve semisynthetic, structurally similar compounds at concentrations of 5000 ng/mL were assayed in the presence of oxycodone and oxymorphone and found not to interfere with identification and quantitation by this method. Finally, exact mass and tandem mass spectrometry techniques were employed to elucidate the structures of the SIM ions.

Hair testing procedures allow a cumulative reflection of long-term drug abuse and are useful as a test for compliance in clinical toxicology. In the present study, liquid chromatography coupled with tandem mass spectrometry was used to determine analgesic opioid drugs in hair samples. The procedure used a simple methanolic extraction, and the evaporated extract was analyzed directly. A selective and sensitive procedure for the simultaneous determination of bisnortilidine, nortilidine, tilidine, buprenorphine, codeine, oxycodone, fentanyl, norfentanyl, hydromorphone, morphine, normorphine, oxymorphone, methadone, piritramide, and tramadol was developed and fully validated. The method fulfilled validation criteria and was shown to be sensitive, with limits of detection ranging from 0.008 to 0.017 ng/mg hair matrix, and precision ranging between 3.1% and 14.9 %. The applicability of the method was shown by analysis of authentic hair samples from patients receiving opioids for the treatment of cancer pain (eg, fentanyl was detected in concentrations up to 0.292 ng/mg, tramadol in concentrations up to 0.612 ng/mg of hair of 1 patient). Hair analysis was shown to be a complementary and useful tool in monitoring the drug-taking behavior of patients consuming opioid analgesics for the treatment of pain. In self-reports and medical records especially, the ingestion of tramadol and methadone was found to be dramatically underreported. In summary, hair analyses gave important additional information for the medical treatment of patients, the results often coming as a surprise to even the attending physicians.

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.This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery.This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women agedor=18 years undergoing abdominal surgery that required aor=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 intensityor=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).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; P0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P0.004 and P0.005, 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; P0.005). 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.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.

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 B6129F 1 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.

Objective To review the pharmacodynamics, pharmacokinetics, efficacy, tolerability, dosing, and role of oral oxymorphone immediate-release (IR) and extended-release (ER). Data source A MEDLINE/PUBMED search (1970 to September 2006) of English language studies. Additional references were obtained from their bibliographies. Study selection All human studies of oxymorphone were reviewed. Data synthesis Oral oxymorphone IR/ER tablet formulations were approved in June 2006. Oxymorphone, a semi-synthetic -opioid receptor agonist structurally similar to hydromorphone, has an oral bioavailability of approximately 10%. Oxymorphone is extensively metabolized to oxymorphone-3-glucuronide and the active 6-hydroxyoxymorphone. Rapid clearance mandates every four- to six-hour dosing (IR) and every 12-hour dosing (ER). Hepatic impairment, renal impairment, and aging enhance systemic exposure. Oxymorphone IR was superior to placebo and oxycodone IR (acute pain studies). Oxymorphone ER was superior to placebo and equivalent to oxycodone CR and morphine CR (one acute and five chronic pain studies). Oxymorphone exhibits the expected opioid side effects, being comparable to oxycodone and morphine in clinical trials. Coadministration with ethanol causes "dose-dumping" (ER) and increases intersubject variability in drug absorption. Oxymorphone IR is indicated for the relief of moderate-to-severe pain, while oxymorphone ER is indicated for persistent pain. Initial doses (opioid-naive) are 10 mg to 20 mg every 4 to 6 hours (IR) and 5 mg every 12 hours (ER). Dosage adjustment is recommended in mild hepatic impairment (Child-Pugh class A), renal impairment (creatinine clearance below 50 mL/min), and in the elderly. Conclusion Oxymorphone is the newest oral opioid to enter a crowded marketplace now totaling 12 Schedule 2 opioids. It does not appear to have any unique assets or liabilities and should be considered as one of many oral opioids for the management of acute and persistent pain of moderate-to-severe intensity.

A method was developed for quantification of oxycodone, noroxycodone, and oxymorphone in small volumes (50 microl) 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 (5 microm, 2.1 mm x 50 mm) 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%).

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 to40 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.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.

Opiates such as hydrocodone, hydromorphone, oxycodone, noroxycodone, and oxymorphone reportedly may interfere with the analysis of morphine and codeine. The analysis of these compounds themselves also is an important issue. Thus, double derivatization approaches utilizing methoxyamine and hydroxylamine to first form oxime products with keto-opiates, followed by the derivatization with trimethylsilyl (TMS) or propionyl groups, have been developed for the simultaneous analysis of these compounds. However, these studies have not included all compounds of interest and resulted in inadequate chromatographic resolution or significant intensity cross-contribution between the ions designating the analyte and its deuterated internal standard for certain compounds. By exploring three-step derivatization approaches with the combination of various derivatization groups and orders, this study concluded that application of methoxyimino/propionyl/TMS groups, in the order listed, facilitated the simultaneous analysis of eight opiates (morphine, 6-acetylmorphine, hydromorphone, oxymorphone, codeine, hydrocodone, oxycodone and noroxycodone) in urine samples, achieving satisfactory limits of quantitation and detection. In addition, the adapted approach resulted in two usable products for morphine and codeine providing alternatives, should interferences render any of these products non-usable.

Condensation of phenylazo-β-ketoamide 4 with oxymorphone 5 afforded an m-iodophenylpyrrolomorphinan (m-IPPM) 6 mediated by elemental zinc in acetic acid/sodium acetate buffer. m-IPPM 6 is a novel opioid receptor agonist (Ki = 4.53 nM for DOP) with high selectivity for DOP receptors. m-IPPM 6 was converted into the positron emitter m-[124I]PPM 8 via the stannylated intermediate 7. The final yield was 24.5 ± 1.9 % (n = 6) with a specific activity of 2.5 ± 1.2 Ci/µmol. Copyright © 2007 John Wiley & Sons, Ltd.

We read with great interest the article entitled ‘Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety’ by Simon and colleagues, published in the April 2015 Issue of Therapeutic Advances in Drug Safety [Simon et al. 2015]. We agree with the authors that Federal abuse-deterrent formulation (ADF) policy does not reflect the urgency of the prescription drug abuse epidemic and does not go far enough toward changing the status quo. We also agree with the authors that policies must also require federal prescription drug benefit plans to cover ADFs to ensure consumers have access to such medications. However, we disagree with the statement ‘ADFs have been proven to reduce prescription drug abuse and its consequences, and even an incremental reduction in abuse can have a significant impact on the nation by reducing the costly social, physical, mental, and public health problems resulting from abuse’. The study by Coplan and colleagues [Coplan et al. 2013] was quoted as the main reference to support the argument by Simon and colleagues that ‘ADF have been proven to reduce prescription drug abuse and its consequences…’. However, in the study by Coplan and colleagues, what was additionally reported was a 20% increase in abuse exposure for other single-entity oxycodone, and 42% increase in abuse exposure for heroin, concomitant with the 36% decrease in abuse exposure for reformulated extended-release (ER) oxycodone (ADF). Coplan and colleagues also acknowledged that reformulating one product’s tablets will not treat opioid addiction, and substitution of other available opioids is likely to consequently occur. Michna and colleagues examined the degree of adherence to the ER opioid, following its switching to a reformulated ER opioid (ADF), and found some patients changed to other ER opioids without abuse-deterrent technology or discontinued ER opioids [Michna et al. 2014]. The conclusion of their study was that abusers may seek more easily abusive alternatives. These include prescription opioids without abuse deterrent technology. Preliminary data suggest that the reformulation of opioids to resist tampering may influence media attention, recreational user preferences, and opioid availability in ways that may in turn alter their attractiveness to recreational users [Romach et al. 2013]. ER oxymorphone abuse has been mentioned in popular media only since recreational users began to recognize it as an alternative to the reformulation of ER oxycodone (ADF), which is designed to be tamper-resistant. Increased public awareness of higher potency with oxymorphone ER and the difficulties of tampering with reformulated ER oxycodone may have lessened abuse of ER oxycodone and made ER oxymorphone a preferred choice for some recreational users [Romach et al. 2013]. Indeed, total oxymorphone prescriptions increased sharply from 268,000 in 2007 to 1.22 million in 2012. In the first quarter of 2011, 325,000 oxymorphone prescriptions were dispensed by retail pharmacies [Drug Enforcement Administration, 2013]. According to the Drug Abuse Warning Network (DAWN ED), total estimated emergency department visits associated with oxymorphone increased from 4599 in 2010 to 12,122 in 2011. The American Association of Poison Control Centers reported 1041 total oxymorphone exposures in 2011, an increase from 169 in 2010 [Drug Enforcement Administration, 2013]. To examine the change in prevalence of prescription opioid abuse after introduction of an abuse-deterrent formulation oxycodone ER in August 2010, Cassidy and colleagues conducted a cross-sectional study, and found significantly greater abuse of oxymorphone ER and buprenorphine, coinciding with the introduction of ADF oxycodone ER [Cassidy et al. 2014]. Cassidy and colleagues conclude that replacement of a widely prescribed opioid with ADF formulation may have had little effect on overall prescription opioid abuse as a class. Another issue of great concern is escalating heroin abuse since the introduction of reformulated ER oxycodone (ADF) to the market. There were 119,000 total users in 2003, but 281,000 by 2011. In addition, first-time past-year use nearly doubled between 2005 and 2011. The death rate of heroin overdose from the 28 states (surveyed) doubled, from 2010 to 2012, from 1.0 to 2.1 per 100,000 [Rudd et al. 2014]. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. In conclusion, at this point, the introduction of ADF opioids has resulted in significantly reduced abuse of those specific ADF opioids after they have fully replaced the original formulations. However, this has resulted in merely a shift away from the ADF opioids to other traditional non-ADF opioids or heroin, and unfortunately, no effect on the overall rates of opioid abuse.

Clinical Question: Is oxycodone associated with greater efficacy and fewer adverse events compared with alternative analgesics for cancer pain?\ud \ud \ud \ud Bottom Line: Oxycodone was not associated with superior cancer pain relief or fewer adverse effects compared with other strong opioids, such as morphine or oxymorphone. However, the quality of the evidence was low.\ud \ud \ud \ud Many patients with cancer experience moderate or severe pain requiring treatment with strong opioids. However, not all opioids are well tolerated by all patients. This JAMA Clinical Evidence Synopsis summarizes a published Cochrane review1 that examined the association of oxycodone (any formulation or route of administration) compared with placebo or an active drug (including alternative forms of oxycodone) for treating cancer pain in adults.

Background: In 2012, a nephrologist reported the development of a multiorgan thrombotic syndromic complex resembling thrombotic thrombocytopenic purpura (TTP) in patients who were abusing long acting oxymorphone hydrochloride; all patients had hemolytic anemia and thrombocytopenia. Objective: Herein, we report another case involving a 31-year-old woman who self intravenously administered dissolved oral oxymorphone resulting in thrombotic sequelae resembling Degos disease. Methods: Formalin-fixed and paraffin embedded skin biopsies were prepared according to standard protocols for H&E and immunohistochemistry. Results: The clinical presentation and biopsy findings were held to be indicative of Degos disease/malignant atrophic papulosis (MAP) but with unusual clinical features including renal failure and severe respiratory insufficiency. Given the efficacy of eculizumab in the treatment of the acute thrombotic phase of Degos disease/MAP, the patient received this drug, resulting in rapid resolution of signs and symptoms associated with her multiorgan failure. Although she developed recurrent cutaneous ulcers despite complete complement inhibition with eculizumab., her other extracutaneous manifestations did not recur. The patient’s pre and post eculizuamb skin biopsies showed a striking pauci-inflammatory thrombogenic vasculopathy associated with marked endothelial cell injury along with deposits of C3d and C4d within the cutaneous vasculature; the C5b-9 deposits were limited to the pre-eculizumab biopsy. We discovered that her syndromic complex was a self-inflicted one related to the localized administration of dissolved oxymorphone. Conclusion: Our patient’s biopsy along with the rapid response to eculizumab indicates that this distinct thrombotic microangiopathy is another complement mediated thrombotic microangiopathy syndrome. Opioid thrombotic microangiopathy has a varied clinical presentation and can mimic other catastrophic microangiopathy syndromes, all of which have in common a responsiveness to complement inhibition.

Concurrent administration of oxycodone and phenytoin may cause, through induction of CYP3A4 enzymes, decreased analgesic effects of oxycodone. However, no descriptions of this interaction exist. A patient who was on oxycodone for chronic back pain was admitted to the hospital. Five days after initiating fosphenytoin, the patient experienced a dramatic escalation in his pain and lack of response to oxycodone breakthrough doses. Changing oxycodone to hydromorphone resulted in significantly improved analgesia. Concurrent use of fosphenytoin and oxycodone may increase the conversion of oxycodone to inactive metabolites, resulting in decreased analgesia. This may be avoided using hydromorphone, morphine, or oxymorphone.

Objective To determine the effects of morphine, methadone, hydromorphone or oxymorphone on the thermal threshold in cats, following buccal and intravenous (IV) administration. Study design Randomized crossover study. Animals Six healthy adult female ovariohysterectomized cats weighing 4.5 ± 0.4 kg. Methods Morphine sulfate (0.2 mg kg −1 IV or 0.5 mg kg −1 buccal), methadone hydrochloride (0.3 mg kg −1 IV or 0.75 mg kg −1 buccal), hydromorphone hydrochloride (0.1 mg kg −1 IV or 0.25 mg kg −1 buccal) or oxymorphone hydrochloride (0.1 mg kg −1 IV or 0.25 mg kg −1 buccal) were administered. All cats were administered all treatments. Skin temperature and thermal threshold were measured in duplicate prior to drug administration, and at various times up to 8 hours after drug administration. The difference between thermal threshold and skin temperature (ΔT) was analyzed. Results Administration of methadone and hydromorphone IV resulted in significant increases in ΔT at 40 minutes after drug administration. Buccal administration of methadone resulted in significant increases in thermal threshold, although no significant difference from baseline measurement was detected at any time point. IV administration of morphine and oxymorphone, and buccal administration of morphine, hydromorphone and oxymorphone did not cause significant thermal antinociception. Conclusion and clinical relevance At the doses used in this study, IV administration of methadone and hydromorphone, and buccal administration of methadone resulted in transient thermal antinociception. The results of this study do not allow us to predict the usefulness of these drugs for providing analgesia in clinical patients.

Oxymorphone, a semisynthetic μ-opioid receptor agonist, is the major active metabolite of oxycodone. It is a highly potent narcotic analgesic due to its high lipid solubility, which allows it to readily cross the blood-brain barrier and enter the central nervous system. It is available as both an immediate-release and extended-release (ER) formulation. Oxymorphone can be abused by injection or inhalation of crushed tablets; thus, in 2011, the manufacturer of ER oxymorphone reformulated the drug with crush-resistant technology to deter its misuse and abuse. We describe the case of a previously healthy, 24-year-old male who experienced reproducible acute subjective bilateral temporary hearing loss that occurred after inhalation of oxymorphone. He presented to the emergency department complaining of acute bilateral hearing loss after he reported snorting a crushed oxymorphone ER 30-mg tablet. Emergency department evaluation revealed obvious bilateral hearing loss as well as coincidental aspiration pneumonia. The patient's medical history revealed that he had experienced a similar episode of hearing loss after a previous episode of oxymorphone inhalation. His hearing loss began to improve 3 hours after presentation to the emergency department and was completely resolved by the following day. Use of the Naranjo adverse drug reaction probability scale revealed oxymorphone to be a probable cause of this patient's acute hearing loss (score of 6). The mechanism of action of opioid-associated hearing loss (OAHL) is not completely understood, but it is thought to be due to disturbances within the cochlea, such as cochlear ischemia. To our knowledge, this is only the second published case report of acute reversible hearing loss following oxymorphone inhalation and the first published case report of reproducible OAHL. Since opioid misuse continues to be prevalent despite attempts at reformulations to make the drugs crush resistant, a high degree of clinical suspicion is needed to evaluate and treat patients who present with unique findings after episodes of substance abuse, especially those related to tamper-resistant formulations.