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.     

Sedative effects of hydromorphone or oxymorphone with or without acepromazine in dogs

Hydromorphone is an agonist opioid with potency approximately five times that of morphine and half that of oxymorphone. The purpose of this study was to compare hydromorphone with oxymorphone, with or without acepromazine, for sedation in dogs, and to measure plasma histamine before and after drug administration. Ten dogs received IM hydromorphone (H; 0.2 mg kg^?1), oxymorphone (O; 0.1 mg kg^?1), hydromorphone with acepromazine (H; 0.2 mg kg^?1, A; 0.05 mg kg^?1) or oxymorphone with acepromazine (O; 0.1 mg kg^?1, A; 0.05 mg kg^?1) in a randomized Latin‐square design. Sedation score, heart rate, respiratory rate, blood pressure, and SpO₂ were recorded at baseline and every 5 minutes after drug administration up to 25 minutes. Plasma histamine was measured at baseline and at 25 minutes post‐drug administration. Data were analyzed with repeated measures anova . Mean ± SD body weight was 21.62 ± 1.54 kg. Mean ± SD age was 1.07 ± 0.19 years. Sedation score was significantly greater for OA after 5 minutes than O alone (4.1 ± 3.5 versus 1.9 ± 1.5) and for HA after 15 minutes than H alone (8.6 ± 2.9 versus 5.9 ± 2.5). There was no significant difference in sedation between H and O at any time point. There was no significant difference between groups at any time with respect to heart rate, respiratory rate, blood pressure or SpO₂. Mean ± SD plasma histamine (nM ml^?1) for all groups was 1.72 ± 2.69 at baseline and 1.13 ± 1.18 at 25 minutes. There was no significant change in plasma histamine concentration in any group. Hydromorphone is effective for sedation in dogs and does not cause measurable increase in histamine. Sedation with hydromorphone is enhanced by acepromazine.     

Cardiovascular effects of epidurally administered oxymorphone and an oxymorphone-bupivacaine combination in halothane-anesthetized dogs

OBJECTIVE: To evaluate cardiovascular effects of epidurally administered oxymorphone (OXY) and an OXY-bupivacaine combination (O/B) in halothane-anesthetized dogs. ANIMALS: 6 dogs. PROCEDURE: In a randomized crossover design study, dogs were anesthetized with halothane and given OXY, O/B, and saline solution (SAL). Eucapnia and end-tidal halothane concentration of 1.2% were established. Heart rate (HR), systemic and pulmonary arterial pressures, central venous pressure (CVP), and cardiac output were measured at baseline and 5, 15, 30, 45, 60, and 75 minutes after treatment. At 90 minutes, glycopyrrolate was administered IV, and measurements were repeated at 95 minutes. Cardiac index (CI), stroke volume, stroke index, systemic vascular resistance (SVR), and left ventricular work were calculated. End-tidal halothane concentration was decreased to 0.8% from 17 to 45 minutes and to 0.5% from 47 to 95 minutes for OXY and O/B, whereas for SAL, it was maintained at 1.5 and 1.2%, respectively. Samples were obtained at 0, 2, 5, 15, 30, 45, 60, and 95 minutes for measurement of serum opiate concentration and comparison with values after IM administration of OXY. RESULTS: HR decreased, but CVP and SVR increased in response to OXY and O/B. These changes were reversed after IV administration of glycopyrrolate, resulting in significant increase in CI, compared with that in response to SAL. Serum opiate concentration increased markedly and peaked within 15 minutes after OXY and O/B administration but did not differ from values after IM administration. CONCLUSIONS: Epidural administration of OXY results in rapid systemic uptake and decreased HR. Glycopyrrolate administration improves HR, resulting in improved CI at equipotent halothane concentrations.     

Cystometry in dogs under oxymorphone and acepromazine restraint

Cystometry was performed in 12 dogs under oxymorphone and acepromazine restraint. A detrusor reflex occurred in 10 of 12 dogs (83%). Mean threshold pressure and volume were 31 cm H2O and 22 ml/kg, respectively. Tonus limb II varied inversely with threshold volume. Threshold volume varied directly with body weight; threshold pressure was independent of body weight.     

Cardiopulmonary and behavioral effects of combinations of acepromazine/butorphanol and acepromazine/oxymorphone in dogs.

Cardiopulmonary and behavioral effects of the following tranquilizer-opioid drug combinations were compared in conscious dogs: acepromazine (0.22 mg/kg of body weight, IV) and butorphanol (0.22 mg/kg, IV); acepromazine (0.22 mg/kg, IM) and butorphanol (0.22 mg/kg, IM); and acepromazine (0.22 mg/kg, IV) and oxymorphone (0.22 mg/kg, IV). Marked sedation and lateral recumbency that required minimal or no restraint was achieved with every drug combination. Analgesia was significantly better in dogs receiving oxymorphone than in dogs receiving butorphanol, as evaluated by response to toe pinch. There were no significant differences between the effects of the 3 drug combinations on heart rate, respiratory rate, arterial blood pressure, body temperature, and arterial pH, PCO2, PO2, and bicarbonate concentration. Heart rate, respiratory rate, and systolic arterial pressure decreased significantly over time with all drug combinations. Total recovery time (minutes from the initial injection to standing) was significantly longer in the dogs given acepromazine and oxymorphone.     

Sedative effects and serum concentrations across time after subcutaneous administration of liposome-encapsulated or standard oxymorphone in healthy dogs

Our lab has developed a slow‐release liposomal formulation of oxymorphone (LEOx). The purpose of this study was to compare sedative effects and serum concentrations of oxymorphone after administration of LEOx and standard oxymorphone (STDOx) to dogs. At baseline, 1 mL of blood was drawn from the cephalic vein and sedation score was recorded. Dogs were divided into four groups (n = 6): (i) LEOx 1.0 mg kg^–1; (ii) LEOx 0.5 mg kg^–1; (iii) STDOx 0.1 mg kg^–1; (iv) STDOx 0.05 mg kg^–1. Unloaded liposomal vehicle (0.5 mL) was used as a control (n = 2). All treatments were given subcutaneously between the scapulae. Sedation score and serum concentration of drug were recorded at 0.5, 1, 2, 4, 8, 12, 16, 24 hours and daily for 5 days. Serum concentrations were measured with ELISA. At all time points, drug was not detected and sedation score was 0 in the control group. Sedation score for group 1 was significantly higher (p < 0.05) at 1 hour than for groups 2,3, and 4. There was no difference in sedation score between treatment groups at any other time. Serum concentrations of drug were significantly higher (p < 0.05) for group 1 at all time points measured after baseline. In groups 2, 3, and 4, serum concentrations of drug fell below the limit of detection (1.5 ng mL^–1) by 24 hours. Serum concentrations after 0.1 mg kg^–1of STDOx were 11.1 ± 3.6 ng mL^–1at 4 hours, which is the recommended time for redosing and presumably reflects the lower end of a therapeutic serum concentration. Serum concentrations were comparable after 1.0 mg kg^–1 of LEOx (10.5 ± 2.4 ng mL^–1) 48 hours after administration. These results suggest that liposomal oxymorphone may provide therapeutic serum concentrations of drug for 2 days after a single subcutaneous administration without undue sedation or other deleterious effects in healthy dogs. Further studies are warranted to assess analgesic efficacy and pharmacokinetics of lipsomal oxymorphone in dogs.     

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

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

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.     

Effects of oxymorphone and hydromorphone on the minimum alveolar concentration of isoflurane in dogs

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

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

The effects of transdermal fentanyl and im oxymorphone on behavioural and physiological responses, after ovariohysterectomy in dogs, were investigated. The study involved three groups of 10 dogs: fentanyl/surgery (FS), oxymorphone/surgery (OS), fentanyl/control (FC). A transdermal fentanyl delivery system (50 μg hour⁻¹) (FS and FC) was applied 20 hours before surgery, or IM oxymorphone (Os) was administered. After ovariohysterectomy (FS and OS) or anaesthesia alone (FC), dogs were continuously videotaped for 24 hours and a standardised hourly interaction with a handler performed. The videotapes were analysed, and interactive and non-interactive behaviours evaluated. In addition, pain and sedation scores, pulse and respiratory rates, rectal temperature, arterial blood pressure, plasma cortisol and plasma fentanyl concentrations were measured. This study showed that transdermal fentanyl and IM oxymorphone (0·05 mg kg⁻¹) produced comparable analgesic effects over a 24 hour recording period. IM oxymorphone produced significantly more sedation and lower rectal temperatures than transdermal fentanyl. There were no significant differences between groups in respiratory and heart rates, and arterial blood pressures.     

End tidal halothane concentration and postoperative analgesia requirements in dogs: a comparison between intravenous oxymorphone and epidural bupivacaine alone and in combination with oxymorphone.

The purpose of this study was to compare the effects of epidural bupivacaine (BUP) and oxymorphone/bupivacaine (O/B) and intravenous (i.v.) oxymorphone (IVO) on halothane requirements during hind end surgery and postoperative analgesia in 24 dogs. Dogs were randomly assigned to treatment groups: O/B--oxymorphone (0.1 mg/kg) in 0.75% bupivacaine (1 mg/kg for a total volume of 0.2 ml/kg); BUP--0.5% bupivacaine (1 mg/kg for a total volume of 0.2 ml/kg) with i.v. oxymorphone (0.05 mg/kg) postoperatively; and IVO--oxymorphone (0.05 mg/kg) pre- and postoperatively. Heart rate (HR), respiratory rate, arterial blood pressure, end-tidal carbon dioxide and halothane, and arterial blood gases were recorded prior to treatment and every 15 minutes thereafter. Once surgery had begun, end-tidal halothane concentrations were decreased as low as possible while still maintaining a stable anesthetic plane. Data were analyzed using ANOVA with P < 0.05 considered significant. End-tidal halothane requirements did not differ significantly among treatments. Respiratory depression was increased and HR was decreased in the O/B and IVO groups. Postoperative analgesic requirements were significantly less in dogs receiving O/B.     

Pharmacokinetics of ammonium sulfate gradient loaded liposome‐encapsulated oxymorphone and hydromorphone in healthy dogs

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

Pharmacokinetics of oxymorphone in cats

Siao, K. T., Pypendop, B. H., Stanley, S. D., Ilkiw, J. E. Pharmacokinetics of oxymorphone in cats. J. vet. Pharmacol. Therap. 34 , 594–598. This study reports the pharmacokinetics of oxymorphone in spayed female cats after intravenous administration. Six healthy adult domestic shorthair spayed female cats were used. Oxymorphone (0.1 mg/kg) was administered intravenously as a bolus. Blood samples were collected immediately prior to oxymorphone administration and at various times up to 480 min following administration. Plasma oxymorphone concentrations were determined by liquid chromatography–mass spectrometry, and plasma oxymorphone concentration–time data were fitted to compartmental models. A three‐compartment model, with input in and elimination from the central compartment, best described the disposition of oxymorphone following intravenous administration. The apparent volume of distribution of the central compartment and apparent volume of distribution at steady state [mean ± SEM (range)] and the clearance and terminal half‐life [harmonic mean ± jackknife pseudo‐SD (range)] were 1.1 ± 0.2 (0.4–1.7) L/kg, 2.5 ± 0.4 (2.4–4.4) L/kg, 26 ± 7 (18–38) mL/min.kg, and 96 ± 49 (62–277) min, respectively. The disposition of oxymorphone in cats is characterized by a moderate volume of distribution and a short terminal half‐life.     

Effect of acepromazine, diazepam, fentanyl-droperidol, and oxymorphone on gastroesophageal sphincter pressure in healthy dogs

Treatment of healthy dogs with 4 commonly used psychotropic or analgesic agents significantly decreased resting gastroesophageal sphincter pressure (GESP). Acepromazine decreased GESP by 35% (P = 0.02); oxymorphone decreased GESP by 38% (P less than 0.005); diazepam decreased GESP by 42% (P = 0.005); and fentanyl-droperidol decreased GESP by 40% (P = 0.03). Therefore, esophageal manometric evaluation of gastroesophageal sphincter function should not be preceded by administration of these drugs.     

A comparison of ketorolac with flunixin, butorphanol, and oxymorphone in controlling postoperative pain in dogs.

Ketorolac tromethamine, a nonsteroidal anti-inflammatory analgesic, was compared with flunixin and butorphanol for its analgesic efficacy and potential side effects after laparotomy or shoulder arthrotomy in dogs. Sixty-four dogs were randomly assigned to receive butorphanol 0.4 mg/kg body weight (BW) (n = 21), flunixin 1.0 mg/kg BW (n = 21), or ketorolac 0.5 mg/kg BW (n = 22), in a double blind fashion. The analgesic efficacy was rated from 1 to 4 (1 = inadequate, 4 = excellent) for each dog. The average scores after laparotomy were ketorolac, 3.4; flunixin, 2.7; and butorphanol, 1.6. After shoulder arthrotomy, the average scores were ketorolac, 3.5; flunixin, 3.0; and butorphanol, 1.4 (5/11 dogs). As butorphanol was unable to control pain after shoulder arthrotomy, oxymorphone, 0.05 mg/kg BW, replaced butorphanol in a subsequent group of dogs and had a score of 2.0 (6/11 dogs). Serum alanine aminotransferase and creatinine were significantly elevated above baseline at 24 hours postoperatively in dogs receiving flunixin. One dog in each group developed melena or hematochezia. One dog receiving ketorolac had histological evidence of gastric ulceration. We concluded that ketorolac is a good analgesic for postoperative pain in dogs.     

Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles

Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid-induced effects of a fivefold overdose of long-acting transdermal fentanyl solution was evaluated in dogs. Twenty-four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 μg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 μg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 μg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 μg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1-3 h following termination of the naloxone dosage regimens. The opioid-induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 μg/kg i.m. naloxone administered at hourly intervals.