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PubMed2004

The use of liquid chromatography/mass spectrometry for quantitative analysis of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue.

Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

Analgesics, Opioid↗

PubMed1995

Oxymorphone-induced analgesia and colonic motility measured in colorectal distension.

Changes in colonic motility in rats following intravenous (IV) oxymorphone (0.1 mg/kg), atropine (0.1 mg/kg), or saline were monitored to determine whether opioid-induced changes in colonic motility affect antinociceptive measurements when using colorectal distension (CRD) as a nociceptive assay. Polygraph recordings of colonic pressures, contraction frequencies, and the pressure-volume relationship of the stimulus showed that oxymorphone produced a transient increase in contraction frequencies when compared to atropine- and saline-treated rats. The transient increase in contraction frequency caused by oxymorphone declined to baseline levels at 30 min after administration, the time at which the nociceptive threshold for CRD was tested. Neither oxymorphone nor atropine changed baseline pressures or the pressure-volume curve for the balloon stimulus. Antinociceptive results from CRD at 30 min posttreatment showed that only oxymorphone produced significant antinociception. We conclude that oxymorphone does not produce changes in colonic motility that complicate antinociceptive measurements in CRD and that CRD is an effective means of testing opioid-induced visceral antinociception.

Analgesics, Opioid↗

PubMed2005

Efficacy and safety of oxymorphone extended release in chronic low back pain: results of a randomized, double-blind, placebo- and active-controlled phase III study.

UNLABELLED: This multicenter, randomized, double-blind, placebo- and active-controlled trial was conducted to compare the analgesic efficacy and safety of oxymorphone extended release (ER) with placebo and oxycodone controlled release (CR) in ambulatory patients with moderate to severe chronic low back pain requiring opioid therapy. Patients (N = 213) aged 18 to 75 years were randomized to receive oxymorphone ER (10 to 110 mg) or oxycodone CR (20 to 220 mg) every 12 hours during a 7- to 14-day dose-titration phase. Patients achieving effective analgesia at a stable opioid dose entered an 18-day double-blind treatment phase and either continued opioid therapy or received placebo. With stable dosing throughout the treatment phase, oxymorphone ER (79.4 mg/day) and oxycodone CR (155 mg/day) were superior to placebo for change from baseline in pain intensity as measured on a visual analog scale; the LS mean differences were -18.21 and 18.55 (95% CI, -25.83 to -10.58 and -26.12 to -10.98, respectively; P = .0001). Use of rescue medication was 20 mg per day. Adverse events for the active drugs were similar; the most frequent were constipation and sedation. Oxymorphone ER and oxycodone CR were generally safe and effective for controlling low back pain. Oxymorphone ER was equianalgesic to oxycodone CR at half the milligram daily dosage, with comparable safety. PERSPECTIVE: Definitive studies of long-acting opioids in patients with chronic low back pain are lacking. We report the results of a multicenter, randomized, placebo-controlled, double-blind study evaluating the analgesic efficacy and safety of oxymorphone ER and oxycodone CR in opioid-experienced patients with chronic low back pain.

Adolescent↗

PubMed2005

Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways.

Two 14-day, randomized, open-label, parallel-group studies examined the effects of extended-release (ER) oxymorphone on CYP2C9 or CYP3A4 metabolic activities in healthy subjects. On days -1, 7, and 14, subjects received either a CYP2C9 probe (tolbutamide 500 mg) or CYP3A4 probes (midazolam and [14C N-methyl]-erythromycin for the erythromycin breath test). Subjects were randomized to 5 groups: high-dose oxymorphone ER (3 x 20 mg q12h) + naltrexone (50 mg q24h); low-dose oxymorphone ER (10-20 mg q12h); rifampin (2 x 300 mg q24h), an inducer of CYP2C9 and CYP3A4 activities; naltrexone (50 mg q24h); or CYP probes alone (controls). Probe metabolism was significantly altered by rifampin on days 7 and 14 (P < .05), whereas probe metabolism was not significantly affected by low-dose oxymorphone ER or by high-dose oxymorphone ER plus naltrexone. Oxymorphone ER exhibits a minimal potential for causing metabolic drug-drug interactions mediated by CYP2C9 or CYP3A4.

Adolescent↗

PubMedDate not supplied

Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit, and dog.

Oxymorphone was extensively metabolized by human, rat, dog, and guinea pig and to a lesser extent by rabbit. The most abundant metabolite in urine for all species was conjugated oxymorphone (12.7-81.7% administered dose) followed by 6 beta- and 6 alpha-carbinols produced by 6-keto reduction of oxymorphone. 6 beta-Oxymorphol (0.2-3.1%) was found in the urine of all species, whereas 6 alpha-oxymorphol (0.1-2.8%) was found only in human, rabbit, and guinea pig. Small amounts of free oxymorphone (less than or equal to 10%) were excreted by all species except rabbit, which excreted 31.7%. Overall recoveries of oxymorphone and metabolites from urine ranged from 15-96%, of which greater than 80% was excreted in the first 24 hr by all species except dog. Only 35% was excreted by dog during the first day. Stereoselectivity of 6-keto- reduction was observed for all species with the 6 beta-carbinol metabolite being most abundant in the urine of all but guinea pig. Considerable individual variability occurred in the excretion of free and conjugated oxymorphone by six human subjects following oral dosing. Species trends in the metabolism of 6-keto-opioids are discussed.

Adult↗

PubMed1997

Intranasal absorption of oxymorphone.

The nasal bioavailability of oxymorphone HCI was determined. Rats were surgically prepared to isolate the nasal cavity, into which a solution of oxymorphone was administered. A reference group of rats was administered oxymorphone HCl intravenously. Plasma oxymorphone concentrations were determined by HPLC. Nasal absorption was rapid, nasal bioavailability was 43%, and the iv and nasal elimination profiles were similar. Oxymorphone HCI appears to have the solubility, potency, and absorption properties required for efficient nasal delivery, which is an alternative to injections.

Administration, Intranasal↗

PubMedDate not supplied

Forensic drug testing for opiates. VI. Urine testing for hydromorphone, hydrocodone, oxymorphone, and oxycodone with commercial opiate immunoassays and gas chromatography-mass spectrometry.

Opiate testing for morphine and codeine is performed routinely in forensic urine drug-testing laboratories in an effort to identify illicit opiate abusers. In addition to heroin, the 6-keto-opioids, including hydromorphone, hydrocodone, oxymorphone, and oxycodone, have high abuse liability and are self-administered by opiate abusers, but only limited information is available on detection of these compounds by current immunoassay and gas chromatographic-mass spectrometric (GC-MS) methods. In this study, single doses of hydromorphone, hydrocodone, oxymorphone, and oxycodone were administered to human subjects, and urine samples were collected before and periodically after dosing. Opiate levels were determined in a quantitative mode with four commercial immunoassays, TDx opiates (TDx), Abuscreen radioimmunoassay (ABUS), Coat-A-Count morphine in urine (CAC), and EMIT d.a.u. opiate assay (EMIT), and by GC-MS. GC-MS assay results indicated that hydromorphone, hydrocodone, oxymorphone, and oxycodone administration resulted in rapid excretion of parent drug and O-demethylated metabolites in urine. Peak concentrations occurred within 8 h after drug administration and declined below 300 ng/mL within 24-48 h. Immunoassay testing indicated that hydromorphone, hydrocodone, and oxycodone, but not oxymorphone, were detectable in urine by TDx and EMIT (300-ng/mL cutoff) for 6-24 h. ABUS detected only hydrocodone, and CAC failed to detect any of the four 6-keto-opioid analgesics. Generally, immunoassays for opiates in urine displayed substantially lower sensitivities for 6-keto-opioids compared with GC-MS. Consequently, urine samples containing low to moderate concentrations of hydromorphone, hydrocodone, oxymorphone, and oxycodone will likely go undetected when tested by conventional immunoassays.

Enzyme Multiplied Immunoassay Technique↗

PubMed2004

Efficacy of oxymorphone extended release in postsurgical pain: a randomized clinical trial in knee arthroplasty.

Patients with moderate or severe pain following knee arthroplasty and washout from standard patient-controlled analgesia (PCA) were randomized to receive 20 mg of an extended-release (ER) oxymorphone formulation (n = 65) or placebo (n = 61) q12h for 1 day. Oxymorphone PCA was used as rescue analgesic. Oxymorphone ER provided significant improvements over placebo for most standard single-dose analgesic parameters, including mean total pain relief (TOTPAR) over 0 to 12 hours (19.30 vs. 13.72; p = 0.0056), as well as for all multiple-dose (24-h) efficacy assessments. Oxymorphone-treated patients used significantly less rescue PCA than those who received placebo (p < 0.02). Adverse events such as nausea and constipation were typical of opioids, and laboratory and physical findings were similar between groups. Oxymorphone ER was effective and generally well tolerated. A single dose was active from 2 hours until > or = 12 hours after administration. Comparisons with other oral opioids are warranted, especially in the setting of outpatient and day surgery.

Adult↗

PubMed2004

Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study.

OBJECTIVE: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain. RESEARCH DESIGN AND METHODS: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (>or= 18 years of age) with moderate or severe cancer pain who were first titrated for 3-10 days with open-label oxymorphone or oxycodone to achieve a stable dose that provided and other efficacy parameters were comparable for adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7-10 days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue. MAIN OUTCOMES AND MEASURES: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect. RESULTS: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores the 2 groups. The mean daily dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15 mg/day). No significant differences in opioid adverse events were observed between the groups. CONCLUSIONS: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.

Adult↗

PubMed2004

Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and dose-proportionality of four dose strengths (5, 10, 20, and 40 mg) of oxymorphone extended release (ER) under both single-dose and steady-state conditions. DESIGN: Randomized, three-period, four-sequence, crossover study. SETTING: Bioavailability clinic. SUBJECTS: Twenty-four healthy adult volunteers. INTERVENTION: Each subject received three of the four possible doses. The three 8-day administration periods were separated by a 7-day washout. Plasma was collected for up to 48 hours after a single dose on day 1 and during a 12-hour dosage interval at steady state. Naltrexone was administered to reduce opioid-related adverse effects. MEASUREMENTS AND MAIN RESULTS: Twenty-three subjects completed at least one study period. Dose-proportionality and linearity were confirmed after single doses (mean oxymorphone ER area under the concentration versus time curve [AUC] 4.54, 8.94, 17.80, and 37.90 ng x hr/ml for 5-, 10-, 20-, and 40-mg doses, respectively) and at steady state (mean oxymorphone ER AUC 5.60, 9.77, 19.3, and 37.0 ng x hr/ml for 5-, 10-, 20-, and 40-mg doses every 12 hrs, respectively). Similar results were found for maximum plasma concentration. Metabolite (6-hydroxyoxymorphone and oxymorphone-3-glucuronide) plasma levels also increased in a linear fashion after single-dose administration and at steady state. CONCLUSION: The pharmacokinetic profile of oxymorphone ER demonstrates linearity and dose-proportionality under single-dose and steady-state conditions for the parent compound and its metabolites for doses of 5-40 mg.

Adult↗

PubMed2003

Oxymorphone--Endo/Penwest: EN 3202, EN 3203.

Penwest Pharmaceuticals and Endo Pharmaceuticals are jointly developing an oral, controlled-release opioid analgesic oxymorphone [EN 3202] using Penwest's TIMERx proprietary drug delivery technology. The product is being developed for twice-a-day dosing in patients with moderate to severe pain. TIMERx is a controlled-release technology based on an agglomerated hydrophilic matrix, which consists of the polysaccharides locust bean gum and xanthan gum. The technology provides a full spectrum of controlled-release profiles lasting >/=4 h. In February 2003, the US FDA has announced that it accepted the NDA for oxymorphone extended-release tablets, oxymorphone ER, for the treatment of moderate to severe pain in patients requiring continuous opioid therapy for an extended period of time. Late in 2002, the Oxymorphone formulation successfully completed a phase III clinical trial in patients with osteoarthritis pain. Another randomised, double-blind, placebo-controlled trial was completed in 127 patients with moderate to severe pain resulting from surgery in the knee. Results demonstrated that patients receiving EN 3202 treatment had significantly superior pain relief compared with placebo recipients. An immediate-release formulation of oxymorphone (EN 3203) has also been accepted by the US FDA.

Analgesics, Opioid↗

PubMed2001

Effects of hydromorphone or oxymorphone, with or without acepromazine, on preanesthetic sedation, physiologic values, and histamine release in dogs.

OBJECTIVE: To compare hydromorphone with oxymorphone, with or without acepromazine, for preanesthetic sedation in dogs and assess changes in plasma concentration of histamine after drug administration. DESIGN: Randomized clinical study. ANIMALS: 10 healthy mixed-breed dogs. PROCEDURE: Dogs were treated IM with hydromorphone (group H), oxymorphone (group O), hydromorphone with acepromazine (group H/A), or oxymorphone with acepromazine (group O/A). Sedation score, heart rate, respiratory rate, systolic blood pressure, and oxygen saturation were recorded at baseline immediately after drug administration (T0) and every 5 minutes for 25 minutes (T25). Plasma histamine concentration was measured at baseline and T25. RESULTS: Sedation was similar between groups H and 0 at all times. Sedation was significantly greater for groups H/A and O/A from T10 to T25, compared with other groups. Systolic blood pressure was significantly reduced at T25 in group H/A, compared with group H, and in group O/A, compared with group O. Prevalence of panting at T25 was 50% for groups H and O, compared with 20% for group H/A and 30% for group O/A. By T25, heart rate was significantly lower in all groups. Oxygen saturation was unaffected by treatment. Mean +/- SD plasma histamine concentration was 1.72 +/- 2.69 ng/ml at baseline and 1.13 +/- 1.18 ng/ml at T25. There was no significant change in plasma histamine concentration in any group. CONCLUSIONS AND CLINICAL RELEVANCE: Hydromorphone is comparable to oxymorphone for preanesthetic sedation in dogs. Sedation is enhanced by acepromazine. Neither hydromorphone nor oxymorphone caused an increase in plasma histamine concentration.

Acepromazine↗

PubMed2004

Evaluation of liposome-encapsulated oxymorphone hydrochloride in mice after splenectomy.

The use of mice in biomedical research is increasing, largely due to the production and use of genetically engineered animals. Providing postoperative pain control in mice presents many challenges, and long-acting analgesic preparations would be advantageous for this species. A single subcutaneous injection of a liposome-encapsulated (LE) preparation of oxymorphone was compared with multiple injections of buprenorphine or saline in outbred mice undergoing splenectomy. Control groups were given isoflurane alone or isoflurane and an injection of LE oxymorphone but did not undergo surgery. The following parameters were evaluated for 5 days after surgery and were compared with presurgical baseline data for each group: food and water consumption, body weight, ethographic score, and voluntary exercise on a running wheel. Ethographic scores indicated less postsurgical pain in both groups of mice that received either analgesic preparation compared with mice that received only saline. However, mice given LE oxymorphone had superior postoperative recovery, as measured by wheel-running distance and body weight gain, compared with mice given buprenorphine or saline. Mice undergoing splenectomy had significant decreases in body weight, food and water consumption, voluntary exercise, and other normal behaviors. Administration of liposomal oxymorphone at the time of surgery improved postsurgical recovery as measured by these parameters compared with multiple injections of buprenorphine or saline alone. Administration of LE oxymorphone at the time of surgery improved postsurgical recovery, as measured by these parameters.

Analgesics, Opioid↗

PubMed1988

Comparison of histamine release induced by morphine and oxymorphone administration in dogs.

Cardiovascular effects (vasodilatation, hypotension) of morphine administration have been attributed to central actions and peripheral histamine release. In the study reported here, we compared plasma histamine (Hm) concentrations after morphine sulfate and oxymorphone HCl administration in conscious dogs. Five healthy adult dogs (mean body weight, 10.1 kg) were randomly administered morphine (2 mg/kg of body weight, IV) or oxymorphone (0.2 mg/kg, IV) by a 5-second bolus injection at weekly intervals. Venous blood samples (5 ml) were collected from jugular veins before and at 1, 2, 5, 15, 30, and 60 minutes after drug administration. Behavioral changes were recorded. Plasma was analyzed by a radioenzymatic technique, using purified histamine N-methyltransferase as an enzyme catalyst (sensitivity of assay, 40 pg Hm/ml). Mean base-line Hm value for all dogs was 0.55 ng/ml. The mean Hm value was significantly higher (P less than 0.05) than the base-line value at 1, 2, 5, 15, and 60 minutes after morphine administration (531.4, 251.0, 113.0, 31.5, and 1.0 ng of Hm/ml, respectively), but there were no significant increases in histamine values from base-line values at any time after oxymorphone administration. All dogs given morphine and 1 dog given oxymorphone showed excitatory behavior; 2 dogs given morphine and 3 dogs given oxymorphone salivated profusely.

Animals↗

PubMed1990

Transdermal oxymorphone formulation development and methods for evaluating flux and lag times for two skin permeation-enhancing vehicles.

Oxymorphone is a candidate for transdermal delivery since it is a very potent analgesic, is not very effective orally, and has a short duration of action. In developing a transdermal delivery system, two criteria that were considered important were achieving adequate flux and minimizing the lag time. Oxymorphone skin permeation rates in vitro were very low unless skin permeation enhancers were included in the vehicle. After an initial screen of 17 formulations, two skin permeation-enhancing formulations were selected for further study. These were myristic acid:propylene glycol:oxymorphone base (A), and decylmethylsulfoxide:ethanol:water:oxymorphone.HCl (B). With either formulation and either human or hairless guinea pig skin, there was little dependence of either in vitro flux or lag time on the section of skin used (stratum corneum, epidermis, epidermis/dermis). There were significant differences between human skin and hairless guinea pig skin when comparing in vitro fluxes with the two formulations. With formulation A, fluxes through hairless guinea pig skin were three-to fivefold greater than through human skin. With B, however, fluxes through human skin were up to fivefold greater than through hairless guinea pig skin. In vitro lag times with A were generally long (approximately 24 h), whereas those with B were much lower (approximately 1 to 10 h). The species dependence of permeation enhancement and the differences in lag time between formulations could be related to differences in the mechanisms of permeation enhancement. In vivo lag times with the fatty acid:propylene glycol vehicle were estimated in hairless guinea pigs based on plasma oxymorphone concentrations. These were much lower than in vitro lag times.

Administration, Cutaneous↗

PubMed2005

Oxymorphone: a review.

Oxymorphone (oxymorphone hydrochloride) (14-hydroxy-dihydromorphinone), a semisynthetic mu-opioid agonist, was first approved by the US Food and Drug Administration in 1959. Oxymorphone is considered a more potent opioid than its parent compound, morphine. Recently, an immediate-release and long-acting oral formulation of this drug was developed that makes oxymorphone a new option in treating moderate to severe pain. This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this new option in treating moderate to severe pain.

Analgesics, Opioid↗

PubMed1987

Oxymorphone-naltrexonazine, a mixed opiate agonist-antagonist.

Previous studies from our laboratories have reported the synthesis and pharmacological characteristics of a series of symmetrical opiate azines: naloxonazine, oxymorphonazine and naltrexonazine. We have now synthesized and characterized in binding assays and in vivo two asymmetrical azines: oxymorphone-naltrexonazine and oxymorphone-3-methoxynaltrexonazine. Oxymorphone-naltrexonazine, which theoretically could interact with the receptor as either an agonist or antagonist, displayed antagonist properties in vitro and in vivo. Oxymorphone-3-methoxynaltrexonazine, which theoretically could bind only as an agonist, possessed agonist properties in binding studies and was a potent analgesic in vivo.

Analgesia↗

PubMedDate not supplied

Comparison of transdermal fentanyl and intramuscular oxymorphone on post-operative behaviour after ovariohysterectomy in dogs.

The effects of transdermal fentanyl and i.m. oxymorphone on behavioural and physiological responses, after ovariohysterectomy in dogs, were investigated. The study involved three groups of 10 dogs: fentanyl/surgery (FS), oxymorphone/surgery (OS), fentanyl/control (FC). A transdermal fentanyl delivery system (50 microg hour(-1)) (FS and FC) was applied 20 hours before surgery, or i.m. oxymorphone (OS) was administered. After ovariohysterectomy (FS and OS) or anaesthesia alone (FC), dogs were continuously videotaped for 24 hours and a standardised hourly interaction with a handler performed. The videotapes were analysed, and interactive and non-interactive behaviours evaluated. In addition, pain and sedation scores, pulse and respiratory rates, rectal temperature, arterial blood pressure, plasma cortisol and plasma fentanyl concentrations were measured. This study showed that transdermal fentanyl and i.m. oxymorphone (0.05 mg kg(-1)) produced comparable analgesic effects over a 24 hour recording period. I.m. oxymorphone produced significantly more sedation and lower rectal temperatures than transdermal fentanyl. There were no significant differences between groups in respiratory and heart rates, and arterial blood pressures.

Administration, Cutaneous↗