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A comparison of morphine, meperidine, and oxymorphone as utilized in patient-controlled analgesia following cesarean delivery.

Seventy-five patients (n = 75) undergoing elective cesarean delivery during epidural anesthesia were randomly assigned to receive one of three opioid analgesics via patient-controlled analgesia (PCA) when they first complained of pain in the recovery room. Following administration of an analgesic loading dose, patients were allowed to self-administer morphine 1.8 mg, meperidine 18 mg, or oxymorphone 0.3 mg iv every 8 min as required. Data collected during the 24-h observation period included visual analog scale (VAS) pain scores at rest and during movement, VAS patient satisfaction scores, total drug administered, the ratio of attempts/injections, and the incidence of nausea/vomiting, sedation, and pruritus. After adjusting for narcotic potency, no differences in 24-h dose requirements were noted between treatment groups (NS). All patients achieved an excellent level of analgesia at rest (NS); however, onset was most rapid with oxymorphone (P less than 0.05). The percentage of patients reporting severe pain during movement was highest in the meperidine group (P less than 0.05). Oxymorphone was associated with the highest incidence of nausea and vomiting (P less than 0.05), whereas increased sedation and pruritus were noted with morphine. Patient satisfaction with drug effect demonstrated significant negative correlations with resting pain scores and degree of sedation. Whereas morphine is a more commonly utilized PCA analgesic, the excellent analgesia, low incidence of sedation, and high patient satisfaction provided by meperidine and oxymorphone suggested useful alternatives.

Adult↗

An evaluation of morphine and oxymorphone administered via patient-controlled analgesia (PCA) or PCA plus basal infusion in postcesarean-delivery patients.

The analgesic efficacy and adverse effects of morphine and oxymorphone in 32 patients who received traditional patient-controlled analgesia (PCA) following cesarean delivery were compared with those in 32 other patients receiving the same agents via PCA plus basal opioid infusion (PCA + BI). All patients were operated upon during epidural anesthesia with 2% lidocaine and 1:200,000 epinephrine to achieve a T4 sensory level. Upon first complaint of pain in the recovery room, patients were given a titrated iv loading dose of the assigned opioid until comfortable and were then provided with a programmable PCA device. Group I (PCA) consisted of two subsets in which incremental boluses of morphine (1.8 mg, n = 16) or oxymorphone (0.3 mg, n = 16) could be self-administered via conventional PCA. Patients in group II (PCA + BI) received a basal infusion of morphine (0.6 mg/hour, n = 16) or oxymorphone (0.1 mg/hour, n = 16) in addition to self-administered boluses of 1.8 and 0.3 mg, respectively. Patients were evaluated for 24 h following initiation of analgesic therapy, and 10-cm visual analog scales (VAS) were utilized at selected intervals to assess pain at rest, pain during movement, and satisfaction with therapy. The level of sedation and incidence of nausea/vomiting and pruritus were also recorded. Patients utilizing PCA + BI noted significant reductions in resting pain scores with oxymorphone and decreased pain during movement with both opioids when compared with individuals using PCA alone (P less than 0.05). There were no significant differences between treatment groups in 24-h dose requirements or patient satisfaction with therapy (P = ns).(ABSTRACT TRUNCATED AT 250 WORDS)

Cesarean Section↗

Safety, tolerability, and effectiveness of oxymorphone extended release for moderate to severe osteoarthritis pain: a one-year study.

A 52-week, multicenter, open-label extension study was performed to evaluate the safety, tolerability, and effectiveness of oxymorphone extended release (ER), a novel tablet formulation of oxymorphone hydrochloride, in 153 patients with moderate to severe chronic osteoarthritis-related pain. Sixty-one patients (39.9%) completed the study. Common opioid-related nonserious adverse events (AEs) caused most withdrawals. However, approximately one-half of withdrawals due to AEs were among opioid-naive patients who received placebo in a previous trial and were started on a dose of 20 mg every 12 hours, suggesting that tolerability can be improved by titrating from a lower initial dose. Mean pain scores initially decreased as previously opioid-naive patients achieved adequate pain relief, reached stable levels after the first 6 weeks, and remained stable at mild levels throughout the remainder of the study (average pain, 20-25 mm on 100-mm Visual Analog Scale). Average daily dosing remained stable throughout the study (median, 40 mg/d). At each assessment, at least 80% of patients rated their global satisfaction with oxymorphone ER as "excellent," "very good," or "good." Oxymorphone ER provides a new 12-hour analgesic for the treatment of moderate to severe chronic osteoarthritis-related pain in patients who may require long-term opioid therapy.

Analgesics, Opioid↗

Cardiopulmonary effects of medetomidine, oxymorphone, or butorphanol in selegiline-treated dogs.

OBJECTIVES: To determine if chronic selegiline HCl administration affects the cardiopulmonary response to medetomidine, oxymorphone, or butorphanol in dogs. STUDY DESIGN: Prospective randomized experimental study. ANIMALS: Twenty-eight adult, random source, hound dogs weighing 21-33 kg. METHODS: Dogs were assigned to the following treatment groups: selegiline + medetomidine (MED; n = 6); placebo + MED (n = 6), selegiline + oxymorphone (OXY; n = 6); placebo + OXY (n = 6); selegiline + butorphanol (BUT; n = 7) or placebo + BUT (n = 6). Nine dogs were treated with two of the three pre-medicants. Dogs were treated with selegiline (1 mg kg(-1) PO, q 24 hours) or placebo for at least 44 days prior to pre-medicant administration. On the day of the experiment, arterial blood for blood gas analysis, blood pressure measurements, ECG, cardiac ultrasound (mM-mode, 2-D, and continuous wave Doppler), and behavioral observations were obtained by blinded observers. An IV injection of MED (750 micro g m(-2)), OXY (0.1 mg kg(-1)) or BUT (0.4 mg kg(-1)) was given. Cardiopulmonary and behavioral data were collected at 1, 2, 5, 15, 30, and 60 minutes after injection. RESULTS: Selegiline did not modify responses to any of the pre-medicant drugs. Medetomidine caused a significant decrease in heart rate (HR), cardiac output (CO), and fractional shortening (FS). Mean arterial pressure (MAP), systemic vascular resistance (SVR), and central venous pressure (CVP) were increased. Level of consciousness and resistance to restraint were both decreased. Oxymorphone did not affect MAP, CO, CVP, or SVR, but RR and PaCO(2) were increased. Level of consciousness and resistance to restraint were decreased. BUT decreased heart rate at 1 and 5 minutes. All other cardiovascular parameters were unchanged. BUT administration was associated with decreased arterial pH and increased PaCO(2). BUT decreased level of consciousness and resistance to restraint. CONCLUSIONS AND CLINICAL RELEVANCE: Although pre-medicants themselves altered cardiopulmonary and behavioral function, selegiline did not affect the response to medetomidine, oxymorphone, or butorphanol in this group of normal dogs.

Animals↗

A quantitative study of [3H]D-Ala2-D-Leu5-enkephalin binding to rat brain membranes. Evidence that oxymorphone is a noncompetitive inhibitor of the lower affinity delta-binding site.

The mechanism by which mu ligands inhibit the binding of prototypic delta agonists to preparations of brain membranes is controversial. Most investigators assume competitive inhibition. In this study, we examine the interaction of the mu agonist oxymorphone and delta agonist DSTLE (D-Ser2-Thr6-Leu-enkephalin) with [3H]D-Ala2-D-Leu5-enkephalin (DADL) binding to membranes of rat brain. According to the two-site competitive model, mu ligands are competitive inhibitors at both sites. The two-site allosteric model supposes that mu ligands are competitive inhibitors at one binding site, and noncompetitive inhibitors at the other binding site. Quantitative analysis of DSTLE and oxymorphone binding demonstrated that the two-site allosteric model fit the data significantly better than did the two-site competitive model, and that oxymorphone is a noncompetitive inhibitor of the lower affinity [3H]DADL-binding site. Autoradiographic studies demonstrated that the lower affinity [3H]DADL-binding site (mu-noncompetitive binding site) had an anatomical distribution apparently indistinguishable from that obtained with [3H]oxymorphone (type I pattern), supporting the hypothesis that the lower affinity delta-binding site is the delta-binding site of an opiate receptor complex consisting of interacting mu- and delta-binding sites.

Animals↗

Ability of flumazenil, butorphanol, and naloxone to reverse the anesthetic effects of oxymorphone-diazepam in dogs.

OBJECTIVE: To evaluate the ability of flumazenil (FLU), butorphanol (BUT), and naloxone (NAL) to reverse the anesthetic effects of oxymorphone-diazepam in dogs. ANIMALS: 6 healthy adult mixed-bread dogs. PROCEDURE: Dogs were randomly assigned to each of 6 reversal treatment groups. In each experiment, oxymorphone (0.22 mg/kg of body weight, i.v.) and diazepam (0.22 mg/kg. i.v.) were given sequentially 15 minutes after glycopyrrolate (0.01 mg/kg, i.v.) administration. Physiologic saline solution (SAL; 1 ml), FLU (0.01 mg/kg), BUT (0.44 mg/kg), or NAL (0.06 mg/kg) alone, or FLU-BUT or FLU-NAL (same dosages) was given i.v. as a reversal treatment 15 minutes after oxymorphone-diazepam administration. An individual unaware of the treatment protocol recorded time to extubation, sternal recumbency, and walking. RESULTS: Time to extubation was significantly (P < 0.05) less with BUT, NAL, FLU-BUT, or FLU-NAL treatment, compared with that for SAL treatment. Time to sternal recumbency was less with BUT, NAL, FLU-BUT, or FLU-NAL treatment, compared with that for SAL treatment. Time to walking was less with FLU-BUT or FLU-NAL treatment, compared with that for SAL treatment. CLINICAL IMPLICATIONS: Flumazenil, in combination with BUT or NAL, can be used to reverse the anesthetic effects of oxymorphone-diazepam in dogs.

Adjuvants, Anesthesia↗

A spirohydantoin derivative of oxymorphone: an agonist with delayed antagonist activity.

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.

Analgesia↗

Chloroacryloyl amides and alpha-methylenelactones from naltrexone, oxymorphone and fentanyl.

A series of chloroacryloyl amides and alpha-methylenelactones were prepared from naltrexone and oxymorphone and some chloroacryloyl amides from fentanyl were prepared as potential Michael acceptors and irreversible ligands. The relative rates of Michael additions of p-methoxybenzenethiol to the double bonds were measured in an NMR spectrometer. The IC50's in rat brain homogenates and the irreversible binding to rat brain membranes were determined. In the methylene-lactone series, it was found that both the alpha and beta isomers derived from naltrexone and oxymorphone were excellent Michael acceptors, but only the beta isomers were more active in the opioid binding assays. The beta isomer derived from naltrexone was an irreversible ligand whereas the oxymorphone analogue was active only in the presence of 100 mM NaCl. In the chloroacryloyl series, only the alpha-chloroacryloyl amide derived from beta naltrexamine proved to be an irreversible binding ligand in the absence of NaCl. It was an excellent Michael acceptor. Under the conditions of our experiments, beta-FNA was a poor Michael acceptor and did not behave as an irreversible ligand in rat membranes.

Acrylates↗

A comparison of oxymorphone and fentanyl as narcotic supplements in general anesthesia.

The safety and efficacy of two potent opiate analgesics, fentanyl and oxymorphone, used as adjuncts in general anesthesia, were studied in 39 patients undergoing elective gynecologic surgery of at least 2 hours duration. Based on a potency ratio of 10:1, patients received either fentanyl 6.5 micrograms/kg or oxymorphone 65 micrograms/kg prior to a thiopental 2 to 3 mg/kg succinylcholine induction and endotracheal intubation. Additional maintenance narcotic and isoflurane were administered as required by the "blinded" anesthesiologist in response to hemodynamic alterations 15% above a presurgical baseline. Overall analysis included hemodynamic response at preset intraoperative intervals, total anesthetic requirements, and stability of vital signs in the recovery room. Blood pressure and heart rate were reliably controlled with either agent; however, less narcotic (ml) and recovery room analgesics were required in the oxymorphone-treated group (p less than 0.05). Decreased naloxone requirements (p less than 0.05) and a more rapid emergence suggested that fentanyl was a safer agent when administered in relatively unrestricted fashion.

Anesthesia, General↗

GC-MS quantitation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in blood.

A method is described for the simultaneous analysis of seven opiates, codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone, in blood samples by gas chromatography-mass spectrometry (GC-MS). One milliliter of blood is combined with an internal standard mixture containing 200 ng of each of the seven deuterated opiates. Two milliliters of acetonitrile is added to precipitate the proteins and cellular material. After centrifugation, the clear supernatant is removed, and the acetonitrile is evaporated. The remaining aqueous portion is adjusted to pH 9 with sodium bicarbonate buffer, and the drugs are extracted into chloroform/ trifluoroethanol (10:1). The organic extractant is transferred and dried under nitrogen. The residue is reconstituted in dilute hydrochloric acid and washed consecutively with hexane and chloroform. The purified aqueous portion is adjusted to pH 9 with bicarbonate buffer, and the drugs are again extracted into chloroform/trifluoroethanol (10:1). The organic portion is removed from the aqueous fraction and dried under nitrogen. The residue is consecutively derivatized with methoxyamine and propionic anhydride using pyridine as a catalyst. The ketone groups on hydrocodone, hydromorphone, oxycodone, and oxymorphone are converted to methoximes. Hydroxyl groups present at the O(3) and O(6) positions of codeine, morphine, 6-acetylmorphine, hydromorphone, and oxymorphone are converted to their respective propionyl esters. After a post-derivatization purification step, the extracts are analyzed by full scan GC-MS using electron impact ionization. The method is linear to at least 2000 ng/mL. Day-to-day precision (N = 15) at 500 ng/mL and 75 ng/mL were less than 10% for all seven targeted opiates. Extraction efficiencies at these two concentrations ranged from 50% to 68%. For each opiate, the limit of quantitation was 10 ng/mL, and the limit of detection was 2 ng/mL.

Analgesics, Opioid↗

Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone.

Human leukocyte and skin mast cell preparations were incubated with morphine sulfate in concentrations ranging from 1.5 X 10(-5) M to 4.5 X 10(-3) M. Skin mast cells also were incubated with oxymorphone and fentanyl in the same concentrations. Human leukocytes did not release histamine in response to any concentration of morphine. In skin mast cells, histamine release by morphine first was detected at 1.5 X 10(-4) M. Histamine release further increased at 5.0 X 10(-4) M with no incremental increase at higher concentrations. Oxymorphone and fentanyl failed to release histamine at any concentration. Histamine release by morphine required calcium but was not influenced by changes in the 1-4 mM range. Skin mast cell preparations were pretreated for 30 min in naloxone 5 X 10(-4) M and then morphine 5 X 10(-4) M was added for 30 min without removing naloxone. Naloxone neither released histamine nor inhibited morphine-induced histamine release. The release of histamine by morphine but not equimolar concentrations of fentanyl and oxymorphone indicates that histamine release by narcotics is not a nonspecific effect of high drug concentration. The failure of naloxone to inhibit morphine-induced histamine release suggests that histamine release by morphine is not dependent on opiate receptor binding or activation. These results indicate that this human mast cell preparation will be useful in further understanding the mechanism of histamine release induced by morphine and other agents.

Cell Membrane↗

Reversal of oxymorphone sedation by naloxone, nalmefene, and butorphanol.

The effects of naloxone (0.4 mg and 1.2 mg intravenously [IV]), nalmefene (0.03 mg/kg IV) and butorphanol (0.2 mg/kg IV and 0.4 mg/kg IV) on oxymorphone-induced sedation were studied in six dogs over a 4-hour observation period. The same dogs were observed for 4 hours untreated (unsedated control) and with oxymorphone sedation followed by saline solution (sedated control). The reversal drug or saline placebo was administered IV 20 minutes after oxymorphone (4.5 mg IV). Blinded observers evaluated the dogs for positional and attitudinal responses, heart rate, and respiratory rate. Sedated dogs treated with nalmefene most closely resembled unsedated dogs in all observed variables. Naloxone was most effective when administered at the higher dose. Mild renarcotization occurred in two dogs at hour 2, even after the higher naloxone dose. Residual sedation was observed in all dogs treated with 0.4 mg naloxone. Butorphanol resulted in partial reversal of sedation at both dosage levels. However, the degree of sedation was significantly less than that observed in the saline-treated controls, and it appeared that 0.4 mg/kg butorphanol may be clinically useful for opiate reversal in some situations.

Animals↗

Epidural vs. intramuscular oxymorphone analgesia after thoracotomy in dogs.

Oxymorphone was administered epidurally (0.1 mg/kg) or intramuscularly (IM) (0.2 mg/kg) to 16 dogs undergoing thoracotomy, to compare the analgesic effectiveness. Heart rate, respiratory rate, systolic and diastolic blood pressure, and pain score were measured hourly. Arterial blood gases were measured at hour 1. A single dose of oxymorphone injected epidurally provided analgesia for up to 10 hours, whereas the IM route provided a comparable effect for less than 2 hours. There were statistically significant increases in heart rate, and systolic and diastolic blood pressures at hour 2 in the dogs treated IM over the dogs treated epidurally. We conclude that epidurally administered oxymorphone is highly effective in alleviating pain after thoracotomy in dogs and provides longer lasting analgesia than the IM route.

Analgesia, Epidural↗

Cardiovascular and pulmonary effects of atropine reversal of oxymorphone-induced bradycardia in dogs.

Oxymorphone was administered intravenously (IV) to 10 dogs (0.4 mg/kg initial dose followed by 0.2 mg/kg three times at 20-minute intervals). Four hours after the last dose of oxymorphone, heart rates were less than 60 bpm in six dogs. After atropine (0.01 mg/kg IV) was administered, heart rate decreased in five dogs and sinus arrhythmia or second degree heart block occurred in four of them. A second injection of atropine (0.01 mg/kg IV) was administered 5 minutes after the first and the heart rates increased to more than 100 bpm in all six dogs. Ten minutes after the second dose of atropine, heart rate, cardiac output, left ventricular minute work, venous admixture, and oxygen transport were significantly increased, whereas stroke volume, central venous pressure, systemic vascular resistance, and oxygen extraction ratio were significantly decreased from pre-atropine values. The PaCO2 increased and the PaO2 decreased but not significantly. The oxymorphone-induced bradycardia did not produce any overtly detrimental effects in these healthy dogs. Atropine reversed the bradycardia and improved measured cardiovascular parameters.

Animals↗

Cardiorespiratory effects of induction and maintenance of anesthesia with ketamine-midazolam combination, with and without prior administration of butorphanol or oxymorphone.

Cardiorespiratory effects of an IV administered bolus of ketamine (7.5 mg/kg of body weight) and midazolam (0.375 mg/kg) followed by IV infusion of ketamine (200 micrograms/kg/min) and midazolam (10 micrograms/kg/min) for 60 minutes was determined in 6 dogs. Ketamine-midazolam combination was administered to dogs on 3 occasions to determine effects of prior administration of IV administered saline solution (1 ml), butorphanol (0.2 mg/kg), or oxymorphone (0.1 mg/kg). The infusion rate of ketamine and midazolam was decreased by 25% for anesthetic maintenance after opioid administration. There were no significant differences in cardiorespiratory variables after saline solution or butorphanol administration; however, oxymorphone caused significant (P < 0.05) increases in mean arterial blood pressure, systemic vascular resistance, and breathing rate. Bolus administration of ketamine-midazolam combination after saline solution caused significant (P < 0.05) increases in heart rate, mean arterial blood pressure, cardiac index, mean pulmonary blood pressure, venous admixture, and significant decreases in stroke index, pulmonary capillary wedge pressure, arterial and mixed venous oxygen tension, arterial oxygen content, and alveolar-arterial oxygen gradient. Opioid administration was associated with significantly (P < 0.05) lower values than was saline administration for heart rate, mean arterial blood pressure, and arterial and mixed venous pH and with higher values for stroke index, pulmonary capillary wedge pressure, and arterial and mixed venous carbon dioxide tension. Prior oxymorphone administration resulted in the highest (P < 0.05) values for mean pulmonary blood pressure, venous admixture, and arterial and mixed venous carbon dioxide tension, and the lowest values for arterial oxygen tension, and arterial and mixed venous pH. Each treatment provided otherwise uncomplicated anesthetic induction, maintenance, and recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Intravenous↗

Operation of long-range substituent effects in rigid opiates: protonated and unprotonated oxymorphone.

The structure of protonated oxymorphone (amine salt) was determined by an X-ray crystallographic study. Significant differences were found with the previously determined structure of unprotonated oxymorphone (free base). Upon protonation on nitrogen, an elongation of the N-C bound occurred, accompanied by subtle changes in bond lengths and angles distant from the site of protonation. These changes in geometry are interpreted as a reflection of long-range substituent effects.

Chemistry, Pharmaceutical↗

Tritiated-6-beta-fluoro-6-desoxy-oxymorphone ([3H]FOXY): a new ligand and photoaffinity probe for the mu opioid receptors.

6-Beta-fluoro-6-desoxy-oxymorphone (FOXY) is a fluorinated derivative of oxymorphone originally developed as a potential PET scanning ligand. Preliminary work (Rothman et al., Neuropeptides 4: 311-317, 1984) demonstrated that [3H]FOXY selectively labeled mu opioid binding sites with low levels of nonspecific binding. In this study the opiate receptor subtypes labeled by [3H]FOXY and [3H]D-ala2-MePhe4, Gly-ol5-enkephalin ([3H] DAGO) were compared using site directed acylating agents and binding surface analysis. Although the data indicated that both ligands selectively label mu opiate receptors, other experiments demonstrated that [3H]DAGO and [3H]FOXY labeled mu binding sites differently. Additional experiments demonstrated that [3H]FOXY can be used as a high yield photoaffinity label for the mu opiate receptor subtype.

Affinity Labels↗

Narcotic-induced histamine release: a comparison of morphine, oxymorphone, and fentanyl infusions.

This study, using an improved histamine assay, repeated previous studies that demonstrated large doses of morphine for induction of anesthesia in patients undergoing coronary artery bypass grafting were associated with histamine release. Thirty randomized patients received infusions of either morphine, 1 mg/kg, oxymorphone, 0.2 mg/kg, or fentanyl, 50 micrograms/kg, over a 10-minute period for induction of anesthesia prior to surgery. There were no significant changes in plasma histamine levels in individual patients or among drug groups. The discrepancy between the present histamine results and those previously reported using similar protocols is due, in part, to variations in plasma histamine measurements that can occur using the less reproducible, older assays for histamine. During routine inductions, large doses of morphine, oxymorphone, or fentanyl administered by infusion do not appear to stimulate release of clinically significant plasma levels of histamine.

Aged↗