oxymorphone and Pain

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

Topics: Analgesics, Opioid; Humans; Models, Biological; Osteoarthritis; Oxycodone; Oxymorphone; Pain; Randomized Controlled Trials as Topic; Tramadol; Treatment Outcome

Pain remains a tremendous burden on patients and for the health care system, with uncontrolled pain being the leading cause of disability in this country. There are a variety of medications that can be used in the treatment of pain, including ketorolac, oxymorphone, tapentadol, and tramadol. Depending on the clinical situation, these drugs can be used as monotherapy or in conjunction with other types of medications in a multimodal approach. A strong appreciation of pharmacologic properties of these agents and potential side effects is warranted for clinicians.

Topics: Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Humans; Ketorolac; Oxymorphone; Pain; Pain Measurement; Phenols; Tapentadol; Tramadol

Abuse-deterrent formulations (ADFs) are technologically sophisticated pharmaceutical formulations that impede manipulation and extraction of opioids and/or provoke unpleasant effects when they are taken in excessive quantity. This is implemented by creating physical barriers, inseparably combining the opioid with an opioid antagonist or adding aversive agents to the formulation. These pharmaceutical changes may potentially alter the pharmacokinetics and consequently the pharmacodynamics of the opioid. In this review, comparative evidence on pharmacokinetic differences between abuse-deterrent and classical formulations of the same opioids is summarized; furthermore, pharmacodynamic differences, with a focus on analgesia and abuse-related symptoms, are addressed. Most of the 12 studies comparing opioid pharmacokinetics have judged the physically intact ADF as being bioequivalent to the corresponding classical formulation. Pharmacokinetic differences have, however, been reported with physically manipulated ADFs and have ranged from moderate deviations from bioequivalence to complete changes in the pharmacokinetic profile (e.g. from a sustained-release formulation to a fast-release formulation). Pharmacodynamic effects were assessed in 14 comparative studies, which reported that intact ADFs usually provided clinically equivalent analgesia and clear advantages with respect to their addiction potential. However, withdrawal symptoms could be induced by the ADFs, although rarely and, in particular, when the ADFs had been physically altered. This evidence suggests that opioid ADFs are a working concept resulting in mostly minor pharmacokinetic and pharmacodynamic differences in comparison with classical formulations; however, they may deviate from this equivalence when physically altered.

Topics: Analgesics, Opioid; Buprenorphine; Chemistry, Pharmaceutical; Humans; Morphine; Oxycodone; Oxymorphone; Pain

Morphine and other opioid morphinans produce analgesia primarily through μ opioid receptors (MORs), which mediate beneficial but also non-beneficial actions. There is a continued search for efficacious opioid analgesics with reduced complications. The cornerstone in the development of 14-alkoxymorphinans as novel analgesic drugs was the synthesis of the highly potent MOR agonist 14-O-methyloxymorphone. This opioid showed high antinociceptive potency but also the adverse effects associated with morphine type compounds. Further developments represent the introduction of a methyl and benzyl group at position 5 of 14-O-methyloxymorphone leading to the strong opioid analgesics 14-methoxymetopon and its 5-benzyl analogue, which exhibited less pronounced side effects than morphine although interacting selectively with MORs. Introduction of arylalkyl substituents such as phenylpropoxy in position 14 led to a series of extremely potent antinociceptive agents with enhanced affinities at all three opioid receptor types. During the past years, medicinal chemistry and opioid research focused increasingly on exploring the therapeutic potential of peripheral opioid receptors by peripheralization of opioids in order to minimize the occurrence of centrally-mediated side effects. Strategies to reduce penetration to the central nervous system (CNS) include chemical modifications that increase hydrophilicity. Zwitterionic 6-amino acid conjugates of 14-Oalkyloxymorphones were developed in an effort to obtain opioid agonists that have limited access to the CNS. These compounds show high antinociceptive potency by interacting with peripheral MORs. Opioid drugs with peripheral site of action represent an important target for the treatment of severe and chronic pain without the adverse actions of centrally acting opioids.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Mice; Oxymorphone; Pain; Rats; Structure-Activity Relationship

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

Topics: Analgesics, Opioid; Chronic Disease; Humans; Low Back Pain; Neoplasms; Osteoarthritis; Oxymorphone; Pain; Randomized Controlled Trials as Topic

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.

Topics: Aged; Aged, 80 and over; Arthralgia; Biotransformation; Clinical Trials as Topic; Constipation; Drug Interactions; Glucuronosyltransferase; Humans; Liver; Narcotics; Nausea; Neoplasms; Opioid-Related Disorders; Oxymorphone; Pain; Pain, Postoperative; Polypharmacy; Receptors, Opioid, mu; Sleep Stages; Vomiting

The undertreatment of acute and chronic pain continues to be a significant health concern in the U.S. Opioids are recommended for the treatment of acute or chronic pain of moderate to severe intensity that is not responsive to other pharmacologic agents, such as nonsteroidal antiinflammatory drugs. A high level of interindividual responses to the analgesic effects and side effects of opioids necessitates the availability of multiple treatment options. Extended-release and immediate-release oral formulations of oxymorphone hydrochloride were recently approved by the U.S. Food and Drug Administration and may provide new options for patients who have not achieved adequate and well-tolerated analgesia with their current opioid. This review provides an overview of the basic pharmacology (including pharmacokinetic and pharmacodynamic profiles), clinical efficacy and tolerability of both oral oxymorphone formulations.

Topics: Analgesics, Opioid; Half-Life; Humans; Molecular Structure; Morphine; Oxymorphone; Pain; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Tablets

For thousands of years, opioids have been used to treat pain, and they continue to be one of the most commonly prescribed medications for pain. It is estimated that 90% of patients presenting to pain centers and receiving treatment in such facilities are on opioids. Opioids can be considered broad-spectrum analgesics that act at multiple points along the pain pathway. Unfortunately, opioids also have the potential for great harm, with multiple side effects and potential complications, some of which are lethal. They are also uniquely addictive, which can lead to misuse and diversion. We reviewed the relevant English literature and did thorough manual searches of the bibliographies of known primary and review articles. We utilized pain relief as the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, improvement in work status, and evidence of addiction. Short-term use and improvement was defined as less than 6 months and long-term relief was defined as 6 months or longer. The 3 systematic reviews evaluating long-term effectiveness of opioids for chronic non-cancer pain provided unclear and weak evidence. The results of this review showed that many patients in the included studies were dissatisfied with adverse events or insufficient pain relief from opioids and withdrew from the studies. For patients able to continue on opioids, evidence was weak suggesting that their pain scores were lower than before therapy and that this relief could be maintained long-term (> 6 months). There was also weak evidence that long-term opioid therapy with morphine and transdermal fentanyl not only decreases pain but also improves functioning. Limited evidence was available for the most commonly used opioids, oxycodone and hydrocodone. Evidence for the ability to drive on chronic opioid therapy was moderate without major side effects or complications. It is concluded that, for long-term opioid therapy of 6 months or longer in managing chronic non-cancer pain, with improvement in function and reduction in pain, there is weak evidence for morphine and transdermal fentanyl. However, there is limited or lack of evidence for all other controlled substances, including the most commonly used drugs, oxycodone and hydrocodone.

Topics: Analgesics, Opioid; Drug Administration Schedule; Fentanyl; Humans; Methadone; Morphine; Oxycodone; Oxymorphone; Pain; Quality of Life; Time Factors; Tramadol

To describe the pharmacology, safety and efficacy, and rationale for use of oral oxymorphone for the management of acute and chronic moderate-to-severe pain.. A PubMed/MEDLINE search (1966-March 2007) was conducted using the following terms: oral oxymorphone, oxymorphone, EN 3202, EN 3203, Opana, and Opana ER. Manufacturer-provided data (package inserts) and abstracts presented at the American Pain Society meetings (2003-2006) were also reviewed.. Human studies evaluating the safety and efficacy of oral oxymorphone in pain management were considered; animal and non-English-language data were excluded.. Oral oxymorphone is a semisynthetic opioid agonist that is specific for the mu-opioid receptor and approved to treat both acute and chronic pain. Unlike other opioids, such as oxycodone, oxymorphone does not bind to the kappa-opioid receptor. Due to extensive liver metabolism, oral oxymorphone is contraindicated in patients with moderate-to-severe hepatic impairment; however, no clinically significant CYP3A4, 2C9, or 2D6 mediated drug-drug interactions have been noted. Elderly patients may experience a 40% increase in plasma concentrations, while renally impaired patients may have a 57-65% increase in bioavailability. Food can increase the rate of absorption by as much as 50%, necessitating dosing either 1 hour before or 2 hours after a meal. Oxymorphone's primary adverse effects are similar to those of other opioids: nausea, vomiting, pruritus, pyrexia, and constipation.. Oxymorphone is an oral therapeutic option approved for the treatment of acute and chronic moderate-to-severe pain. Oxymorphone has a safety and efficacy profile similar to that of other commonly used pure opioids (morphine, oxycodone, hydromorphone). Like oxycodone and morphine, oxymorphone also has immediate-release and extended-release formulations. Since cost alone is not yet favorable for oxymorphone over oxycodone or morphine, further studies of comparative efficacy targeting potential advantages of oxymorphone over other opioids are necessary before considering it for addition to a formulary.

Topics: Administration, Oral; Delayed-Action Preparations; Disease Management; Humans; Oxymorphone; Pain; Pain Measurement

To review the pharmacodynamics, pharmacokinetics, efficacy, tolerability, dosing, and role of oral oxymorphone immediate-release (IR) and extended-release (ER).. A MEDLINE/PUBMED search (1970 to September 2006) of English language studies. Additional references were obtained from their bibliographies.. All human studies of oxymorphone were reviewed.. 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-naïve) 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.. 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.

Topics: Administration, Oral; Aged; Analgesics, Opioid; Delayed-Action Preparations; Drug Interactions; Humans; Oxymorphone; Pain; Pain Measurement; Randomized Controlled Trials as Topic

Opana ER (oxymorphone extended release [ER]) is a new oral long-acting formulation indicated for the treatment of moderate to severe chronic pain. Because the ER matrix slowly releases oxymorphone over 12 h, consistent plasma levels are produced with low peak-to-trough fluctuations. Oxymorphone ER is the only long-acting opioid that contains oxymorphone, which exhibits some distinct pharmacologic properties compared with most other opioids, including a longer half-life, higher affinity for the micro-opioid receptor, and lack of interaction with the CYPP450 drug-metabolizing system. With a safety and tolerability profile similar to other opioids and documented efficacy in several models of chronic pain (low back, cancer, and osteoarthritis), oxymorphone ER provides a new option for clinicians and patients in the treatment of chronic pain.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Chronic Disease; Delayed-Action Preparations; Drug and Narcotic Control; Humans; Oxymorphone; Pain; Patient Selection; Severity of Illness Index; Treatment Outcome

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.

Topics: Analgesics, Opioid; Drug Administration Schedule; Drug Interactions; Humans; Neoplasms; Oxymorphone; Pain

Butorphanol (Stadol) is a synthetic agonist-antagonist analgesic from the 14-hydroxymorphinan series. Animal studies display analgesia, antitussive effects, low gastrointestinal activity, limited respiratory depression, some cardiovascular and skeletal muscle actions, diuresis, slight miosis and opiate antagonism. Butorphanol is metabolized in the liver with renal excretion, yielding a half-life of 3-4 h. Pain relief is good to excellent with parenteral administration in 90% of patients with moderate to severe pain. Surgical anesthetic indications involve preoperative and preinduction supplementation, balanced anesthesia and postoperative pain. Side effects are sedation, nausea, elevated pulmonary vascular pressures and rarely CNS excitation. Limited respiratory depression exists. Butorphanol is a potent analgesic agent with a favorable side effect profile.

Topics: Anesthesia; Animals; Antitussive Agents; Butorphanol; Chemical Phenomena; Chemistry; Depression, Chemical; Diuretics; Dose-Response Relationship, Drug; Humans; Morphinans; Morphine; Naloxone; Nausea; Oxymorphone; Pain; Pulmonary Wedge Pressure; Rats; Respiration; Substance-Related Disorders

Oxymorphone is a semisynthetic μ-opioid agonist, marketed as a prescription analgesic purported to be twice as potent as oxycodone for pain relief. Oral formulations of oxymorphone were reintroduced in the United States in 2006 and reports of abuse ensued; however, there are limited data available on its pharmacodynamic effects. The current study aimed to examine the direct physiologic effects, relative abuse liability, analgesic profile and overall pharmacodynamic potency of oxymorphone in comparison with identical doses of oxycodone. Healthy, non-dependent opioid abusers (n = 9) were enrolled in this within-subject, double-blind, placebo-controlled, 3-week inpatient study. Seven experimental sessions (6.5 hours) were conducted, during which an oral dose of immediate-release formulations of oxymorphone (10, 20 and 40 mg), oxycodone (10, 20 and 40 mg) or placebo was administered. An array of physiologic, abuse liability and experimental pain measures was collected. At identical doses, oxymorphone produced approximately twofold less potent effects on miosis, compared with oxycodone. Oxymorphone also produced lesser magnitude effects on measures of respiratory depression, two experimental pain models and observer-rated agonist effects. However, 40 mg of oxymorphone was similar to 40 mg of oxycodone on several abuse-related subjective ratings. Formal relative potency analyses were largely invalid because of the substantially greater effects of oxycodone. Overall, oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone. These data suggest that the published clinical equianalgesic estimates may not be consistent with the observed direct physiologic effects of opioids, results of experimental pain models or abuse liability measures, as assessed in the human laboratory.

Topics: Administration, Oral; Adult; Analgesics, Opioid; Blood Pressure; Cognition; Cold Temperature; Cross-Over Studies; Double-Blind Method; Female; Heart Rate; Humans; Male; Opioid-Related Disorders; Oxymorphone; Pain; Pain Measurement; Pressure

Randomized, double-blind, placebo-controlled, single-dose crossover study.. To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis.. Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations.. Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking-induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire.. The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA-placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66]).. This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication.. 2.

Topics: Acetaminophen; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Cross-Over Studies; Dextropropoxyphene; Disability Evaluation; Double-Blind Method; Drug Combinations; Early Termination of Clinical Trials; Female; Humans; Intermittent Claudication; Kaplan-Meier Estimate; Lumbar Vertebrae; Male; Middle Aged; Minnesota; Oxymorphone; Pain; Pain Measurement; Safety-Based Drug Withdrawals; Spinal Stenosis; Surveys and Questionnaires; Time Factors; Treatment Outcome

Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone.. This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3.. Aprepitant increased the area under the plasma concentration-time curve (AUC0-8) of oxycodone by 25% (p<0.001) and of oxymorphone by 34% (p<0.001), as well as decreased the AUC0-8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001) and of oxymorphone by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p = 0.02) at day 3 compared to day 1.. The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose.. UMIN.ac.jp UMIN000003580.

Topics: Adult; Aged; Analgesics, Opioid; Aprepitant; Area Under Curve; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphinans; Morpholines; Neoplasms; Oxycodone; Oxymorphone; Pain

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

Topics: Aged; Analgesics, Opioid; Cachexia; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain

Assay sensitivity remains a significant issue in pain clinical trials. One possible method for increasing assay sensitivity for detecting changes in pain intensity is to increase the reliability of pain intensity assessment by increasing the number of intensity ratings obtained, and combining these ratings into composite scores. The current study performed secondary analyses from a published clinical trial to test this possibility. The reliability and assay sensitivity pain intensity scores made up of 1 to 9 24-hour pain intensity recall ratings were compared. Although the reliability of the outcome measures improved as the number of items increased, this increase in reliability was not associated with an increase in assay sensitivity. A single 24-hour recall rating was about as valid (sensitive) for detecting treatment effects as composite scores made up of 2 to 9 different ratings. If this finding replicates in other pain populations, it has significant implications for the design and conduct of pain clinical trials. Specifically, it suggests the possibility that assessment burden (and associated costs and problems related to missing data) might be greatly reduced by specifying a single recall rating as the primary outcome variable. Research is needed to explore this possibility further.

Topics: Adult; Analgesics, Opioid; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Oxymorphone; Pain; Pain Measurement; Reproducibility of Results; Time Factors

This study examined the effect of amantadine, an N-methyl-d-aspartate receptor antagonist, on the thermal antinociceptive effect of oxymorphone in cats. Six adult healthy cats were used. After baseline thermal threshold determinations, oxymorphone was administered intravenously to maintain plasma oxymorphone concentrations of 10, 20, 50, 100, 200, and 400 ng/mL. In addition, amantadine, or an equivalent volume of saline, was administered intravenously to maintain a plasma amantadine concentration of 1100 ng/mL. Thermal threshold and plasma oxymorphone and amantadine concentrations were determined at each target plasma oxymorphone concentration. Effect maximum models were fitted to the oxymorphone concentration-thermal threshold data, after transformation in % maximum response. Oxymorphone increased skin temperature, thermal threshold, and thermal excursion (i.e., the difference between thermal threshold and skin temperature) in a concentration-dependent manner. No significant difference was found between the amantadine and saline treatments. Mean ± SE oxymorphone EC(50) were 14.2 ± 1.2 and 24.2 ± 7.4 ng/mL in the amantadine and saline groups, respectively. These values were not significantly different. Large differences in oxymorphone EC(50) in the saline and amantadine treatment groups were observed in two cats. These results suggest that amantadine may decrease the antinociceptive dose of oxymorphone in some, but not all, cats.

Topics: Amantadine; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Cats; Dose-Response Relationship, Drug; Drug Interactions; Female; Hot Temperature; Oxymorphone; Pain

Oxycodone is widely used for the treatment of cancer pain, but little is known of its pharmacokinetics in cancer pain patients. The aim of this study was to explore the relationships between ordinary patient characteristics and serum concentrations of oxycodone and the ratios noroxycodone or oxymorphone/oxycodone in cancer patients.. Four hundred and thirty-nine patients using oral oxycodone for cancer pain were included. The patients' characteristics (sex, age, body mass index [BMI], Karnofsky performance status, "time since starting opioids", "oxycodone total daily dose", "time from last oxycodone dose", use of CYP3A4 inducer/inhibitor, "use of systemic steroids", "number of medications taken in the last 24 h", glomerular filtration rate (GFR) and albumin serum concentrations) influence on oxycodone serum concentrations or metabolite/oxycodone ratios were explored by multiple regression analyses.. Sex, CYP3A4 inducers/inhibitors, total daily dose, and "time from last oxycodone dose" predicted oxycodone concentrations. CYP3A4 inducers, total daily dose, and "number of medications taken in the last 24 h" predicted the oxymorphone/oxycodone ratio. Total daily dose, "time from last dose to blood sample", albumin, sex, CYP3A4 inducers/inhibitors, steroids, BMI and GFR predicted the noroxycodone/oxycodone ratio.. Women had lower oxycodone serum concentrations than men. CYP3A4 inducers/inhibitors should be used with caution as these are predicted to have a significant impact on oxycodone pharmacokinetics. Other characteristics explained only minor parts of the variability of the outcomes.

Topics: Analgesics, Opioid; Cross-Sectional Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Linear Models; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Sex Factors

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.

Topics: Adult; Analgesics, Opioid; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP2D6; Double-Blind Method; Electric Stimulation; Female; Humans; Male; Oxycodone; Oxymorphone; Pain; Pain Measurement; Pain Threshold; Polymorphism, Genetic; Young Adult

Assess the effectiveness and tolerability of a program of gradual dose titration with oxymorphone extended release (ER) for treatment of moderate to severe chronic pain in opioid-naive patients.. Open-label, nonrandomized 6-month study with a titration/stabilization period of 50%) reductions of pain interference with quality-of-life measures. There was minimal dose escalation over the 5 months and low use of rescue medication.. Oxymorphone ER provided effective pain relief from moderate to severe chronic pain in opioid-naive patients. Gradual titration was well tolerated, with a low rate of discontinuations caused by AEs.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Female; Humans; Longitudinal Studies; Male; Middle Aged; Oxymorphone; Pain; Pain Measurement; Treatment Outcome; United States

A minor pathway for the biotransformation of morphine to hydromorphone has been identified in humans. Recently, an unsubstantiated claim that morphine is metabolized to hydromorphone and then to oxymorphone was published. The goal of this study was to determine if credible evidence that oxymorphone is a metabolite of either morphine or hydromorphone exists. Urine specimens from pain patients who were treated exclusively with high daily doses of morphine (N = 34) or hydromorphone (N = 26) were analyzed by liquid chromatography-tandem mass spectrometry for oxymorphone, hydromorphone, and morphine (LOD = 25 ng/mL). Specimens were also tested for a variety of other medications. Criteria for inclusion of patients' specimens were as follows: 1. patients were undergoing exclusive dosing with either morphine or hydromorphone; 2. non-prescribed medications were not detected; and 3. urine concentrations of morphine were > 100,000 ng/mL for the high-dose morphine group and > 1,000 ng/mL of hydromorphone for the high-dose hydromorphone group. Consistent with earlier reports, hydromorphone was detected in patients treated with high-dose morphine. The ratio of hydromorphone to morphine ranged from 0.2 to 2.2%. Oxymorphone was not detected in any specimen from high-dose morphine or high-dose hydromorphone patients. The authors conclude, based on these data, that oxymorphone is not a metabolite of morphine or hydromorphone.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Hydromorphone; Male; Middle Aged; Morphine; Oxymorphone; Pain

Inadequate analgesia and/or unmanageable adverse events frequently result in the need to rotate patients with cancer pain to a different opioid. The availability of a novel oral extended-release (ER) formulation of oxymorphone provides clinicians with another treatment option. In this study, we assessed the analgesic effectiveness and safety of the new oral ER formulation of oxymorphone following treatment with controlled-release (CR) morphine sulfate or oxycodone.. Adults with moderate to severe cancer pain were stabilized for > or =3 days on morphine CR or oxycodone CR, and then treated for 7 days at their stabilized dose. Drug selection was based upon patients' previous use or investigator preference. Patients were then crossed over for 7 days of treatment at an estimated equianalgesic dosage of oxymorphone ER. Pain was assessed using a visual analog scale, and adverse events were recorded.. A total of 86 patients entered open-label treatment. Of 34 patients assigned to morphine CR and 52 assigned to oxycodone CR, 21 (61.8%) and 42 (80.8%) completed stabilization and began treatment with oxymorphone ER, respectively; 59 of 63 (93.7%) completed treatment with oxymorphone. There were no significant differences in daily pain intensity scores between oxymorphone ER and comparators (paired t -test). Rescue medication use, expressed as the percent of the daily dose of scheduled opioid, was greater during morphine CR treatment than after crossover to oxymorphone ER (25.2% vs 13.3%; P <0.05, Wilcoxon's test). The tolerability/safety profiles (e.g., nausea, drowsiness, somnolence) were similar for all opioids.. Cancer patients stabilized on morphine CR or oxycodone CR were safely and rapidly converted to a lower milligram dose of oxymorphone ER that provided adequate pain relief with comparable tolerability. These results justify additional trials with oxymorphone ER.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Cross-Over Studies; Delayed-Action Preparations; Humans; Middle Aged; Morphine; Neoplasms; Oxymorphone; Pain; Pain Measurement; Pilot Projects; Prospective Studies; Quality of Life

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.. 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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neoplasms; Oxycodone; Oxymorphone; Pain; United States

Thirty patients with cancer pain completed a double-blind crossover study comparing controlled-release (CR) and immediate-release (IR) oxycodone. In open-label titration (2 to 21 days), these patients were stabilized on IR oxycodone qid. They were then randomized to double-blind treatment with CR oxycodone q12h or IR oxycodone qid for 3 to 7 days followed by crossover at the same daily dose. Mean (+/- SD) pain intensity (0 = none to 10 = severe) decreased from a baseline of 6.0 +/- 2.2 to 2.7 +/- 1.1 after titration with IR oxycodone dosed qid. Pain intensity remained stable throughout double-blind treatment: 2.7 +/- 1.9 with CR oxycodone and 2.8 +/- 1.9 with IR oxycodone. Acceptability of therapy and pain scores correlated with plasma oxycodone concentrations for each interval and were similar for both medications (IR and CR oxycodone). Adverse events were similar for both formulations. Following repeat dosing under double-blind conditions, oral CR oxycodone administered q12h provided analgesia comparable to IR oxycodone given qid.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biological Availability; Chronic Disease; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Pain Measurement; Therapeutic Equivalency; Vomiting

The relative analgesic potency of oral and intramuscular oxymorphone was evaluated in a double-blind crossover comparison of graded single doses in patients with chronic pain due to cancer. When both duration and intensity of analgesia are considered (total effect), oral oxymorphone was 1/6 as potent as the intramuscular form. In terms of peak effect, however, oral oxymorphone was only 1/14 as potent. These values are almost identical to those obtained in a previous study comparing oral with intramuscular morphine. The analgesic effect of oral oxymorphone rose to a peak later and had a longer duration than the effect of intramuscular oxymorphone. Intramuscular oxymorphone and morphine were also compared in a similar patient group. Intramuscular oxymorphone proved to be 8.7 times as potent as morphine in terms of total analgesic effect and 13 times as potent in terms of peak effect. In roughly equinalgesic doses, the occurrence of side effects was qualitatively and quantitatively similar for oral and intramuscular oxymorphone and for intramuscular oxymorphone and morphine.

Topics: Administration, Oral; Adult; Aged; Analgesics; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Hydromorphone; Injections, Intramuscular; Male; Middle Aged; Morphine; Neoplasms; Oxymorphone; Pain; Placebos; Time Factors

Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone.. A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.. Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC. Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.

Topics: Analgesics, Opioid; Chromatography, Liquid; Humans; Male; Oxycodone; Oxymorphone; Pain; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Tandem Mass Spectrometry

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

Topics: Analgesia; Analgesics, Opioid; Animals; Brain; Cytochrome P-450 Enzyme System; Estradiol; Estrous Cycle; Female; Male; Oxycodone; Oxymorphone; Pain; Progesterone; Propranolol; Rats; Rats, Wistar

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

Topics: Analgesics, Opioid; Female; Gastrostomy; Humans; Male; Middle Aged; Neoplasms; Oxymorphone; Pain; Retrospective Studies

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

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Male; Morphine; Naltrexone; Narcotic Antagonists; Oxymorphone; Pain; Pain Measurement; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Reinforcement, Psychology; Self Administration

Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent μ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure-activity relationships on a series of zwitterionic analogues of 1 (14- O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.

Topics: Analgesics, Opioid; Animals; Cell Membrane; Dipeptides; Humans; Male; Mice; Morphine; Oxymorphone; Pain; Protein Binding; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands.

Topics: Analgesics; Animals; Benzylidene Compounds; Ligands; Mice; Oxymorphone; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu

The introduction of extended-release opioid analgesics helped initiate an epidemic of prescription opioid abuse in the United States. To make access to the drug by crushing or dissolution more difficult, abuse-deterrent formulations (ADFs) of OxyContin (Purdue Pharma, Stamford, CT) and Opana ER (Endo Pharmaceuticals Inc., Malvern, PA), which use the same foundation technology (Intac, Grunenthal, Aachen, Germany), were introduced in 2010 and 2012, respectively. To examine their relative effectiveness, we used a structured survey of 12,124 individuals entering treatment for opioid use disorder followed by a more focused online survey with a subset of these patients (N = 129) using both structured and open-ended questions. Data showed that the OxyContin ADF was highly effective in reducing nonoral abuse (91.4% before the ADF, 47.9% afterwards), particularly with insufflation (78%-28.8%) and intravenous injection of the active drug (42.7%-21.4%). However, although the Opana ER ADF was effective in reducing insufflation (80%-37.1%), injection (60.0%-51.4%), and overall nonoral abuse (94.3%-77.1%), it showed no significant decrease over time. Bearing in mind that the Opana ER sample was smaller in size than that for OxyContin, our results nonetheless suggest disparate outcomes resulting from the introduction of the ADFs, which could indicate that an ADF's effectiveness may be drug-specific. Given the public health impact of prescription opioids and the considerable effort being expended to develop ADFs as a partial solution to the problem, our preliminary studies suggest that each ADF must be evaluated on its own merits even if the same proprietary technology is used.

Topics: Adult; Analgesics, Opioid; Delayed-Action Preparations; Drug Compounding; Female; Humans; Male; Opioid-Related Disorders; Oxycodone; Oxymorphone; Pain; Treatment Outcome

Oxycodone is an opioid analgesic metabolized to oxymorphone and noroxycodone by cytochrome P450 (CYP) 2D6 and 3A4/5, respectively. This was a retrospective study to evaluate sex, age, urinary pH and concurrent medication use on oxycodone, oxymorphone and noroxycodone distributions. Urine specimens obtained from patients on chronic opioid therapy were analyzed by LC-MS-MS. There were 108,923 specimens from a subject's first or single visit, who were at least 18 years of age, and had documented physician-reported oxycodone use. The majority of specimens had detectable oxycodone urine concentrations (n = 106,852) resulting in oxycodone mole fractions (arithmetic mean ± SD) of 0.44 ± 0.27. Ninety-eight percent (n = 106,229) and 49% (n = 53,394) had detectable oxymorphone and noroxycodone, respectively. Oxycodone and oxymorphone mole fractions were lower in women compared with men (P < 0.0001). Mean ± SD age was 49.1 ± 12.9 years. Noroxycodone mole fractions were highest in the 65 years and older age group. Concurrent use of a CYP2D6 inhibitor, but not a CYP3A4/5 inhibitor, altered oxycodone and oxymorphone mole fractions. Dual inhibition of CYP2D6 and CYP3A4/5 did not result in a statistical difference upon comparison with CYP2D6 inhibitor or CYP3A4/5 inhibitor use. Patient factors affect oxycodone and metabolite mole fractions and suggest increased awareness of each contribution when attempting to monitor therapy with urine drug testing.

Topics: Adolescent; Adult; Age Factors; Aged; Analgesics, Opioid; Chromatography, Liquid; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Morphinans; Oxycodone; Oxymorphone; Pain; Retrospective Studies; Sex Factors; Specimen Handling; Tandem Mass Spectrometry; Young Adult

The aim of this study is to evaluate the pharmacokinetic profile of oxycodone and three of its metabolites, noroxycodone, oxymorphone and noroxymorphone after intravenous administration in Chinese patients with pain.. Forty-two subjects were assigned to receive intravenous administration of oxycodone hydrochloride of 2.5, 5 or 10 mg. Plasma and urine samples were collected for up to 24 h after intravenous administration of oxycodone hydrochloride.. Pharmacokinetic parameters showed that mean values of C(max), AUC(0-t) and AUC(0-∞) of oxycodone were dose dependent, whereas Tmax and t(1/2) were not. The mean AUC(0-t) ratio of noroxycodone to oxycodone ranged from 0.35 to 0.42 over three doses, and those of noroxymorphone, or oxymorphone, to oxycodone were ranging of 0.06-0.08 and 0.007-0.008, respectively. Oxycodone and its three metabolites were excreted from urine. Approximately 10% of unchanged oxycodone was recovered in 24 h. Most adverse events (AEs) reported were mild to moderate. The frequently occurred AEs were dizziness, nausea, vomiting, drowsiness and fatigue. No dose-related AEs were found.. Our pharmacokinetics of oxycodone injection in Chinese patients with pain strongly support continued development of oxycodone as an effective analgesic drug in China.

Topics: Adult; Analgesics, Opioid; Area Under Curve; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morphinans; Oxycodone; Oxymorphone; Pain

Topics: Analgesics, Opioid; Female; Humans; Male; Morphinans; Oxycodone; Oxymorphone; Pain

Topics: Analgesics, Opioid; Female; Humans; Male; Morphinans; Oxycodone; Oxymorphone; Pain

To understand the factors that contribute to patient and physician global outcome ratings and the extent to which receiving different doses of opioids or placebo might influence the importance of these factors better.. A secondary analysis was performed using data from a prospective, multicenter, double-blind placebo-controlled, and active-controlled parallel group dose-ranging study comparing the efficacy of oxymorphone extended release (ER) 20 mg (ER20, N=121); oxymorphone ER 40 mg (ER40, N=121); oxycodone controlled release 20 mg (Oxy20, N=125); and placebo (N=124) in a sample of patients with osteoarthritis. We performed 2 regression analyses to identify the predictors of pretreatment to posttreatment improvement in patient and physician global ratings of arthritis status.. Improvement in global ratings of arthritis status was strongly associated with a decrease in pain intensity. Pretreatment to posttreatment improvement in physical and psychological functioning made independent contributions to the prediction of both criterion variables.. The findings underscore the importance of change in pain intensity as a key correlate of ratings of global improvement. However, pain intensity is not the only important factor. In the current sample, improvement in both physical and psychological functioning made independent contributions to improvements in ratings of osteoarthritis status, supporting global ratings as assessing multicomponent domains. Overall, the findings suggest that when a patient or physician reports that the patient is "doing better," the patient is likely reporting less pain intensity and engaging in more physical activity and feeling better emotionally.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Osteoarthritis; Outcome Assessment, Health Care; Oxymorphone; Pain; Pain Measurement; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

The object of this study was to evaluate the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and Feb 2010. The observed excretion was modeled using logarithmic transformation and approximated a Gaussian distribution. Oxycodone excretion into urine had a geometric mean of 1.93 mg/g of creatinine and oxymorphone had a value of 0.41 mg/g of creatinine. Increasing concentrations of oxycodone correlated with a smaller proportion of oxymorphone excretion suggesting saturation of oxycodone metabolism. Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 ± 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 ± 1.1%) in the population. Samples with concentrations of oxycodone above 10 mg/g of creatinine showed a sub-population of subjects with metabolic ratios roughly 100-fold less than the linear predictive model in this study. This study describes typical ranges for oxycodone and oxymorphone in urine, and showed that it is possible to identify fast or slow metabolizers who may be at risk for adverse events.

Topics: Analgesics, Opioid; Chromatography, High Pressure Liquid; Humans; Models, Biological; Oxycodone; Oxymorphone; Pain; Reference Values; Reproducibility of Results; Retrospective Studies; Tandem Mass Spectrometry; Time Factors

Oxymorphone is a pure μ-opioid receptor agonist that is commonly used in nonhuman primate medicine and surgery to minimize pain ranging in intensity from moderate to severe. We compared pharmacokinetic profiles and physiologic and behavioral responses to oxymorphone between titi monkeys (Callicebus spp.) and rhesus macaques (Macaca mulatta). Titi monkeys (n = 4) and rhesus macaques (n = 4) were injected intravenously with either a bolus of 0.075 mg/kg oxymorphone or placebo on multiple occasions, with a minimal washout period of 14 d between trials. Blood collection was limited to no more than 3 samples per trial, with samples collected at multiple time points until 10 h after injection. Collection periods, animal order, and testing day were randomized. In addition, macaques underwent a single serial collection at all time points to validate study design. A 2-compartment model best described the disposition of oxymorphone in both species. Clearance was faster in macaques than titi monkeys, in which terminal half-life was longer. Statistically significant physiologic differences were found between species and between treatments within species. Apart from these effects, oxymorphone did not significantly change physiologic parameters over time. After oxymorphone treatment, macaques demonstrated behaviors reflecting pruritis, whereas titi monkeys exhibited sedation. Despite its mild side effects, we recommend the consideration of oxymorphone for pain management protocols in both Old and New World nonhuman primates.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Injections, Intravenous; Macaca mulatta; Male; Motor Activity; Oxymorphone; Pain; Pitheciidae; Pruritus; Species Specificity

The utilization of high-potency opioids is an important component of chronic pain management, and appropriate utilization of these medicines is a common concern of payers. Two of the most commonly prescribed oral long-acting opioids, oxycodone controlled-release (CR) and oxymorphone extended-release (ER), are FDA-approved for twice-daily dosing, which equates to a theoretical average consumption (DACON) of 2 tablets per day. DACON values greater than 2 have budget and policy implications for managed care pharmacists.. To assess from the perspective of the pharmacy benefit decision maker the DACONs of oxycodone CR and oxymorphone ER.. The main outcome measure for the analysis was DACON. Pharmacy and medical claims data from a large commercially insured population (i3 InVision Data Mart database) were analyzed to identify patients with at least 1 pharmacy claim for either oxycodone CR or oxymorphone ER from July 1, 2007, to September 30, 2009. After an initial 30-day titration period, all subjects included in the study had 1 or more claims totaling at least a 90-day supply of either study drug during the subsequent 90 days (DACON measurement period). Patients were excluded if there was evidence of a switch from one to the other study opioid during the 90-day measurement period. There were no limitations on the use of other opioids, either short- or long-acting, during either the DACON measurement period or the previous 6 months (baseline period). In addition, patients were excluded if the enrollee was younger than 18 years old, pregnant, did not have continuous insurance coverage for the 6 months before and after the start of the 90-day DACON measurement, or were enrolled in an HMO plan. Bivariate analyses were performed with between-group differences in DACON values assessed using t-tests and Wilcoxon rank sum tests. Patient characteristics including age, sex, geographic location, and baseline Charlson Comorbidity Index (CCI) for each drug group were evaluated descriptively using either the Pearson chi-square test or t-test. Multivariate analyses were conducted using generalized linear models (GLM) to adjust for the observed heterogeneity among patients in the observational database. For the GLMs, the gamma distribution and log link function were chosen to account for non-normal distributions of DACON. Independent variables included study drug, tablet strengths, age, sex, CCI, the maximum days gap between prescription refills during the DACON measurement period, and other opioid medication use. Several sensitivity analyses were conducted to verify all findings.. The final analyses were conducted on 6,567 oxycodone CR patients and 796 oxymorphone ER patients. The unadjusted DACON mean value for the highest strength of oxycodone CR 80 milligrams (mg) was 3.9, compared with 2.9 for oxymorphone ER 40 mg (P < 0.001); mean DACON values were 3.0 versus 2.4, respectively, for lower strengths (P < 0.001) and 3.1 versus 2.5 for all strengths (P < 0.001). After adjusting for age, sex, CCI, maximum gap days, and other opioid medication use, a risk-adjusted mean difference in DACON remained, with oxycodone CR patients receiving on average 0.6 tablets more per day than those dispensed oxymorphone ER (P < 0.001). The direction, magnitude, and statistical significance of these differences were essentially unchanged in sensitivity analyses.. On average during a 90-day time period, patients taking oxymorphone ER consumed 0.6 fewer tablets per day than did patients taking oxycodone CR. Further research is necessary to see if this difference amounts to cost savings for health plans that provide prescription reimbursement for patients with chronic pain syndromes.

Topics: Administration, Oral; Analgesics, Opioid; Chi-Square Distribution; Chronic Disease; Cost Savings; Delayed-Action Preparations; Drug Costs; Drug Prescriptions; Drug Utilization Review; Female; Humans; Insurance, Pharmaceutical Services; Linear Models; Male; Managed Care Programs; Middle Aged; Multivariate Analysis; Oxycodone; Oxymorphone; Pain; Practice Patterns, Physicians'; Retrospective Studies; Tablets; Time Factors; United States

14-O-Methyloxymorphone and 14-methoxymetopon were reported as highly selective and potent micro opioid receptor agonists. The aim of this study was to demonstrate the opioid activity of these compounds in vitro and in vivo in comparison to oxymorphone, morphine and DAMGO. The micro opioid receptor efficacy, full or partial agonist nature of opioids was analyzed in the rat vas deferens (RVD) bioassay. Compared to oxymorphone, 14-O-methyloxymorphone and 14-methoxymetopon showed greater affinities to the rodent brain micro opioid receptors in receptor binding assays. In isolated organs 14-O-methyloxymorphone and 14-methoxymetopon were 3-10-fold more potent than the micro agonist opioid peptide, DAMGO. All tested compounds reached at least 70% maximum inhibition in mouse vas deferens (MVD) except morphine and oxymorphone. In the RVD, morphine could not exceed 50% inhibition of the twitches while 14-O-methyloxymorphone and 14-methoxymetopon showed inhibitory effects more than 70%. Oxymorphone reached only 4% maximal agonist effect and antagonized the inhibitory effect of DAMGO. The investigated morphinans produced dose-dependent antinociceptive activities in mice and rats. Both, 14-O-methyloxymorphone and 14-methoxymetopon are highly efficacious micro opioid receptor agonists in the RVD exhibiting full micro agonist properties. The RVD tissue contains mu receptors indicated by the comparable K(e) values of the micro antagonist naltrexone against DAMGO in the MVD. RVD may be a good alternative to assess the mu receptor efficacy of opioid agonists providing a more physiological environment for the ligand-receptor interaction than other efficacy measuring methods such as the [(35)S]GTPgammaS binding assay.

Topics: Analgesics, Opioid; Animals; Brain; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Mice; Mice, Inbred Strains; Models, Biological; Morphine; Morphine Derivatives; Naltrexone; Oxymorphone; Pain; Rats; Rats, Wistar; Receptors, Opioid, mu; Vas Deferens

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.

Topics: Analgesics, Opioid; Chromatography, Liquid; Codeine; False Negative Reactions; Forensic Toxicology; Humans; Hydrocodone; Medication Adherence; Morphinans; Oxycodone; Oxymorphone; Pain; Tandem Mass Spectrometry

Topics: Analgesics, Opioid; Clinical Trials as Topic; Humans; Oxymorphone; Pain

To examine the development of analgesic tolerance in patients on oxymorphone extended-release (OxymER).. 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.. 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).. Main outcome measures included OxymER doses (pill counts) and pain intensity ratings using a visual analog scale at monthly visits.. There were significant dose increases from weeks 1 to 2 and 2 to 6 (P < 0.05). Doses stabilized around week 6, suggesting the completion of what we defined as "titration." Both doses and pain ratings were stable when this titration phase was excluded from the analysis (P = 0.751; P = 0.056, respectively). Only 28% of the patients had any dose changes following this titration. While there was a significantly greater dose at week 52 compared with week 10 (P = 0.010), the increase in dose became insignificant after excluding four subjects who required two dose increases (P = 0.103).. The results showed that most of the titration/dose stabilization changes occurred within the first 10 weeks. A minority (28%) of subjects required dosage increases after this (defined) titration period. Pain reports stabilized statistically after 2 weeks. The findings of this post hoc analysis suggest a lack of opioid tolerance in the majority (72%) of these OA patients who completed this study following a defined titration period on OxymER.. This post hoc analysis of oxymorphone ER consumption in osteoarthritis pain vs pain report showed that most dose changes occurred during an initial "titration period" as defined. Following this titration few subjects increased dose and analgesia remained stable. These findings suggest a lack of longitudinal opioid tolerance in the majority of those OA subjects who completed the trial.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Tolerance; Female; Humans; Longitudinal Studies; Male; Middle Aged; Multicenter Studies as Topic; Osteoarthritis, Hip; Osteoarthritis, Knee; Oxymorphone; Pain; Pain Measurement; Prospective Studies; Treatment Outcome

Topics: Administration, Oral; Analgesics, Opioid; Biological Availability; Clinical Trials as Topic; Delayed-Action Preparations; Drug Administration Schedule; Drug Interactions; Humans; Low Back Pain; Neoplasms; Opioid-Related Disorders; Osteoarthritis; Oxymorphone; Pain; Pain, Postoperative

Topics: Analgesics, Opioid; Cannabidiol; Cannabinoids; Carbazoles; Chronic Disease; Dronabinol; Drug Combinations; Humans; Ibuprofen; Oxycodone; Oxymorphone; Pain; Plant Extracts; Serotonin Receptor Agonists; Tryptamines

Antinociception achieved after peripheral administration of opioids has opened a new approach to the treatment of severe and chronic pain. Additionally, opioid analgesics with restricted access to the central nervous system could improve safety of opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and neuropathic pain. Their antinociceptive activities were compared with those of morphine, the classical mu-opioid receptor agonist. Intraplantar administration of morphine and the 6-amino acid derivatives produced dose-dependent reduction of formalin-induced flinching of the inflamed paw, without significant effect on the paw edema. Local i.pl. administration of the new derivatives in rats with neuropathic pain induced by sciatic nerve ligation produced antiallodynic and antihyperalgesic effects; however, the antinociceptive activity was lower than that observed in inflammatory pain. In both models, the 6-amino acid derivatives and morphine at doses that produced analgesia after i.pl. administration were systemically (s.c.) much less active indicating that the antinociceptive action is due to a local effect. Moreover, the local opioid antinociceptive effects were significantly attenuated by naloxone methiodide, a peripherally acting opioid receptor antagonist, demonstrating that the effect was mediated by peripheral opioid receptors. The present data indicate that the peripherally restricted 6-amino acid conjugates of 14-O-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in neuropathic pain. Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting pain.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Hyperalgesia; Inflammation; Male; Morphine; Naloxone; Neuralgia; Oxymorphone; Pain; Rats; Rats, Wistar; Structure-Activity Relationship

Treatment of pain with opioids is limited by their potential abuse liability. In an effort to develop analgesics without this side effect, a series of bivalent ligands containing a mu-opioid receptor agonist pharmacophore connected to a delta-opioid receptor antagonist pharmacophore through variable-length spacers (16-21 atoms) was synthesized. Members of this series [mu-opioid receptor (M)-delta-opioid receptor (D)-agonist (A)-antagonists (N): MDANs] are antinociceptive in the tail flick assay, but antinociceptive tolerance and physical dependence do not develop to ligands having spacers with 19-21 atoms. The current studies compared the rewarding properties of three bivalent ligands (MDAN-16, -19 and -21) and a mu-opioid receptor agonist (MA-19) to those of morphine in the conditioned place preference assay in mice after i.v. administration. Place preference developed to morphine and to MA-19, but not to the MDANs. The responses to MDAN-16 were highly variable, although place preference of borderline significance appeared to develop. Reinstatement was also evaluated after extinguishing morphine conditioned place preference; morphine and MA-19, but not the MDANs, reinstated morphine conditioned place preference. Taken together, these results suggest that the bivalents are less rewarding compared to morphine in opioid-naïve mice and do not induce reinstatement in previously morphine-preferring mice. The lack of a conditioned place preference response for MDAN-19 and -21, compared to the equivocal results with MDAN-16, suggests a minimum distance requirement between mu-opioid receptor and delta-opioid receptor recognition sites. This requirement may reflect the binding of MDAN-19 and -21 to mu-opioid receptor-delta-opioid receptor heterodimeric receptors that block reward but not antinociception.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Conditioning, Psychological; Ligands; Male; Mice; Mice, Inbred ICR; Morphine; Naltrexone; Narcotic Antagonists; Oxymorphone; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu

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 (mu, delta, and kappa) 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.

Topics: Analgesics, Opioid; Animals; Data Interpretation, Statistical; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Mice; Mice, Knockout; Morphine; Oxymorphone; Pain; Pain Measurement; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid

Topics: Administration, Oral; Analgesics, Opioid; Drug Costs; Formularies as Topic; Humans; Managed Care Programs; Oxymorphone; Pain

Opiates are commonly used to treat moderate to severe pain and can be used over prolonged periods in states of chronic pain such as those associated with cancer. In addition, to analgesic actions, studies show that opiate administration can paradoxically induce hyperalgesia. At the pre-clinical level, such hyperalgesia is associated with numerous pronociceptive neuroplastic changes within the primary afferent fibers and the spinal cord. In rodents, sustained opiate administration also induces antinociceptive tolerance. The mechanisms by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear. The present study was aimed at determining whether sustained opiate-induced hyperalgesia, associated neuroplasticity and antinociceptive tolerance are the result of specific opiate interaction at opiate receptors. Enantiomers of oxymorphone, a mu opioid receptor agonist, were administered to rats by spinal infusion across 7 days. Sustained spinal administration of (-)-oxymorphone, but not its inactive enantiomer (+)-oxymorphone or vehicle, upregulated spinal dynorphin content, produced thermal and tactile hypersensitivity, and produced antinociceptive tolerance. These results indicate that these pronociceptive actions of sustained opiate administration require specific interaction with opiate receptors and are unlikely to be the result of accumulation of potentially excitatory metabolic products. While the precise mechanisms, which may account for these pronociceptive changes remain to be unraveled, the present data point to plasticity initiated by opiate receptor interaction.

Topics: Afferent Pathways; Animals; Central Nervous System; Disease Models, Animal; Drug Administration Schedule; Drug Tolerance; Dynorphins; Hyperalgesia; Isomerism; Male; Narcotics; Neuronal Plasticity; Nociceptors; Oxymorphone; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, mu; Spinal Nerve Roots; Up-Regulation

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.

Topics: Analgesics, Opioid; Animals; Animals, Outbred Strains; Behavior, Animal; Body Weight; Buprenorphine; Drinking; Eating; Injections, Subcutaneous; Laboratory Animal Science; Liposomes; Male; Mice; Mice, Inbred ICR; Oxymorphone; Pain; Pain Measurement; Physical Conditioning, Animal; Specific Pathogen-Free Organisms; Splenectomy

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butorphanol; Dog Diseases; Dogs; Drug Therapy, Combination; Ketoprofen; Oxymorphone; Pain; Pain Measurement; Vocalization, Animal

The antinociceptive activities of morphine, and its quaternary analogue methylmorphine, have been compared after intraperitoneal and intracerebroventricular administrations in the mouse paw formalin test. Systemic morphine inhibited both the early and late phases of the formalin-induced licking response and this activity was naloxone sensitive. In contrast, systemic methylmorphine inhibited only the late phase, and this activity was blocked by pre-treatment with methylnaloxone. Central administration of either morphine or methylmorphine inhibited the early phase of the licking response partially and the late phase completely. Systemic naloxone inhibited the central action of both opioids, whilst systemic methylnaloxone did not affect the central action of methylmorphine. The results indicate that the early phase of the response to formalin in the mouse may be inhibited by stimulation of central opioid receptors whilst inhibition of the late phase may involve both peripheral and central opioid receptors.

Topics: Analgesics; Animals; Codeine; Dose-Response Relationship, Drug; Formaldehyde; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Morphine; Narcotic Antagonists; Oxymorphone; Pain; Pain Measurement

Quaternary derivatives of naloxone and other compounds are assumed not to enter the central nervous system following systemic administration. We report that i.p. naloxone methylbromide (5 mg/kg) completely reversed the antinociceptive effect of systemically administered morphine (6 mg/kg) in acutely spinalised rats, although it had no effect in the same animals prior to the transection. Naloxone hydrochloride was effective both before and after transection. Nuclear resonance spectra confirmed the purity of both compounds. These results suggest that acute spinal transection allows rapid entry of quaternary naloxone into the spinal cord. Quaternary compounds therefore may need to be used with caution in spinalised animals.

Topics: Animals; Denervation; Female; Hydromorphone; Morphine; Oxymorphone; Pain; Permeability; Rats; Rats, Inbred Strains; Spinal Cord

A series of beta-naltrexamine and beta-oxymorphamine derivatives that contain ionizable moieties coupled to the 6 beta-amino group were synthesized in an effort to develop antagonists and agonists that have negligible access into the central nervous system (CNS). Among the beta-naltrexamine derivatives 1-7, all displayed partial agonism on the guinea pig ileal longitudinal muscle preparation except for aspartyl derivative 6, which was a full agonist with activity in the range of morphine. The beta-oxymorphamine derivatives 8-12 were all full agonists with potencies ranging from 1.5 to 6.1 times that of morphine. Among the compounds evaluated in mice for antinociceptive or opioid antagonist activities, aspartyl derivative 6 possessed the greatest difference between peripheral (po or iv) and icv equiactive antagonist doses. Compared to naltrexone, 6 was greater than 100 times more potent by the icv route, but 6000-10,000 times less potent when administered po or icv. The present study suggests that zwitterionic groups are highly effective in preventing penetration of ligands into the CNS. Such ligands may be useful pharmacologic tools for investigation of peripheral opioid mechanisms. Moreover, they could find clinical applications when the central actions are unwanted.

Topics: Animals; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Guinea Pigs; Hydromorphone; Male; Mice; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Oxymorphone; Pain; Structure-Activity Relationship

We have synthesized a novel derivative of oxymorphone, oxymorphone-6 alpha-spirohydantoin. The derivative was less toxic in mice than the parent compound and it showed a significant anticonvulsive activity. It exerted agonist effects in doses lower than those of morphine and its agonist effects were longer lasting. Furthermore, both oxymorphone and the 6-spirohydantoin showed definite antagonist properties 48 hr later: they prevented analgesic effects of morphine. The antagonist effects of the derivative persisted for a week.

Topics: Analgesia; Animals; Anticonvulsants; Behavior, Animal; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation, Preclinical; Hydantoins; Hydromorphone; Male; Mice; Morphine; Oxymorphone; Pain; Sensory Thresholds; Time Factors

Both naloxone hydrochloride and the quaternary compound, naloxone methylbromide, significantly reduced antinociception elicited by 90 s of continuous footshock. Peripheral specificity of quaternary naloxone was demonstrated by its lack of antagonism of morphine analgesia. These results suggest that a significant portion of the antinociception elicited by these parameters of footshock and assessed by tail-flick procedures in rats is due to the activation of peripheral endorphins.

Topics: Analgesia; Animals; Drug Interactions; Electroshock; Hydromorphone; Male; Morphine; Oxymorphone; Pain; Rats; Rats, Inbred Strains; Reaction Time; Stress, Physiological

An equine model, subjected to three kinds of pain (superficial, deep, and visceral) was used to test effects of analgesic drugs. Two groups of ponies were used. In the first group of six ponies, six drugs (fentanyl, meperidine, methadone, oxymorphone, pentazocine, and xylazine) were given according to a Latin square experimental design, and tests were made at 30-minute intervals for 4 hours. Mean values (control) for the three kinds of pain were obtained before and after the tests and were compared with the mean values (drugs) obtained over 2- and 4-hour intervals (four and eight measurements per interval, respectively). Xylazine was significantly more effective in obtunding deep pain (P less than 0.05) at 2- and 4-hour intervals than were the other drugs. Significant differences were not found between values for controls and values for drugs tested for relief of superficial and visceral pain at 2- and 4-hour intervals. In the second group of four ponies, the drug (xylazine) determined most effective in group 1 ponies was given alone or in combination with the next most effective drugs (fentanyl, meperidine, and oxymorphone). Data were obtained in the same manner as for the first group. Mean values were calculated for 2- and 4-hour intervals, and the variance was analyzed. Xylazine and fentanyl combined had the best 2- and 4-hour performance for the relief of visceral pain in the second group (P less than 0.1). Neither xylazine nor a combination of drugs differed markedly from control values for 2- and 4-hour intervals for relief of superficial and deep pain.

Topics: Analgesics; Animals; Disease Models, Animal; Female; Fentanyl; Horse Diseases; Horses; Male; Meperidine; Methadone; Oxymorphone; Pain; Pentazocine; Xylazine

Topics: Action Potentials; Animals; Brain Stem; Chlorpromazine; Levorphanol; Male; Methadone; Morphine; Naloxone; Oxymorphone; Pain; Pentobarbital; Rats; Reticular Formation

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Codeine; Humans; Hydromorphone; Meperidine; Methadone; Morphine; Narcotics; Oxymorphone; Pain; Phenazocine; Piperidines

Topics: Adolescent; Geriatrics; Humans; Hydromorphone; Meperidine; Oxymorphone; Pain; Toxicology

Topics: Analgesia; Humans; Hydromorphone; Oxymorphone; Pain; Pain Management