Use of a von Frey device for evaluation of pharmacokinetics and pharmacodynamics of morphine after intravenous administration as an infusion or multiple doses in dogs

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of morphine after IV administration as an infusion or multiple doses in dogs by use of a von Frey (vF) device. ANIMALS: 6 dogs. PROCEDURE: In the first 2 crossover experiments of a 3-way crossover study, morphine or saline (0.9%) solution was administered via IV infusion. Loading doses and infusion rates were administered to attain targeted plasma concentrations of 10, 20, 30, and 40 ng/mL. In the third experiment, morphine (0.5 mg/kg) was administered IV every 2 hours for 3 doses. The vF thresholds were measured hourly for 8 hours. Plasma concentrations of morphine were measured by high-pressure liquid chromatography. RESULTS: No significant changes in vF thresholds were observed during infusion of saline solution. The vF thresholds were significantly increased from 5 to 8 hours during the infusion phase, corresponding to targeted morphine plasma concentrations > 30 ng/mL and infusion rates > or = 0.15 +/- 0.02 mg/kg/h.The maximal effect (EMAX) was 78 +/- 11% (percentage change from baseline), and the effective concentration to attain a 50% maximal response (EC50) was 29.5 +/- 5.4 ng/mL. The vF thresholds were significantly increased from 1 to 7 hours during the multiple-dose phase; the EC50 and EMAX were 23.9 +/- 4.7 ng/mL and 173 +/- 58%, respectively. No significant differences in half-life, volume of distribution, or clearance between the first and last dose of morphine were detected. CONCLUSIONS AND CLINICAL RELEVANCE: Morphine administered via IV infusion (0.15 +/- 0.02 mg/kg/h) and multiple doses (0.5 mg/kg, IV, every 2 hours for 3 doses) maintained significant antinociception in dogs.     

Pharmocokinetic and pharmacodynamic evaluation of intravenous morphine in dogs

Morphine is considered the prototypical opiate analgesic. Despite the common use of morphine in dogs, ideal dosing strategies have not been formulated due to the difficulty in assessing its analgesic effects. The purpose of this study was to: 1) evaluate a noninvasive mechanical threshold device (von Frey device) to measure antinociceptive responses (pharmacodynamics) of opiates in dogs and 2) evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous (IV) morphine in dogs. Six healthy Beagle dogs were used. The von Frey threshold (vFT) response was evaluated hourly for 8 hours in each dog to examine the effect of repeated testing (controls). PK and PD (vFT) measurements were then made following a 1 mg kg^–1 IV bolus of morphine sulfate. A two way blinded crossover consisted of an 8 hour IV constant rate infusion of saline or morphine with hourly PD measurements. The individual CRI was based on individual PK data and adjusted every 2 hours to attain targeted plasma concentrations of morphine of 10, 20, 30, and 40 ng mL^–1. Blood samples were taken hourly in all phases, except the controls. No significant (p > 0.05) intraindividual changes in vFT occurred in the controls over 8 hours. The morphine bolus produced increased vFT at 1, 2, 3, and 4 hours post injection (p < 0.05). The E_MAX and EC₅₀ following the IV bolus were 213 ± 104% (increase from baseline) and 13.9 ± 5.8 ng mL^–1, respectively. The CRI produced increased vFT at plasma concentrations >30 ng mL^–1, when compared to saline controls (p < 0.05). Targeted plasma concentrations were inconsistent at higher infusion rates, suggesting the PK of morphine may change during CRI. The actual mean ± SD CRI plasma concentrations (ng ml^–1) were 10.8 ± 3.0, 22.7 ± 7.4, 32.4 ± 13.9, 35.7 ± 16.9. Morphine dosing protocols should be re‐evaluated, as sufficient analgesia may not be obtained from published dosages. Intravenous boluses may be more predictable than CRI.     

Antinociceptive effects of epidural magnesium sulphate alone and in combination with morphine in dogs

ObjectiveTo compare the antinociceptive effects of magnesium sulphate (MgSO₄) when administered epidurally alone and in combination with morphine.Study designExperimental, randomized, ‘blinded’, crossover study.AnimalsSix healthy adult Beagle dogs.MethodsEvaluated treatments were MgSO₄ (2.5 mg kg⁻¹) alone (Mg), morphine (0.1 mg kg⁻¹) alone (Mo), MgSO₄ in combination with morphine (Mm), and sterile water (0.115 mL kg⁻¹; Co) that were injected in the lumbosacral epidural space using an epidural catheter. Antinociception was measured using the von Frey mechanical threshold device applied to the carpal pads, both sides of the thorax and metatarsi. Measurements were obtained at time points: before treatment (baseline) and 0.5, 1, 2, 4, 6, 12, 18 and 24 hours after the epidural injection. Sedation, behaviour score and presence of motor deficits were assessed. Data were analyzed using a linear mixed model and Bonferroni adjustments, with significance set at p < 0.05.ResultsThere were significant effects of treatment and time in all regions. Overall threshold values in grammes force [median (interquartile range)] when stimulation regions were combined were significantly higher in Mg [164 (135–200)], Mo [156 (129–195)] and Mm [158 (131–192)] compared to Co [145 (120–179)]. Thresholds were significantly higher compared to Co in Mg, Mo and Mm at the thorax and metatarsi, but only in Mg and Mo at the carpal pads. No motor deficits were observed at any time point. Thresholds (combined regions) were increased from baseline at one or more time points with all treatments, including control.Conclusion and clinical relevanceEpidural MgSO₄ produced an antinociceptive effect characterised by an increase in the mechanical thresholds of similar magnitude to that produced by epidural morphine, compared with the control group, without causing any motor deficits. No potentiation of morphine antinociception was observed. The onset and offset times of antinociception could not be clearly established. To what extent these results can be extrapolated to clinical cases requires further investigation.     

Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide following morphine administration to dogs

The purpose of this study was to evaluate the pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) following morphine administered intravenously and orally to dogs in a randomized crossover design. Six healthy 3–4-year-old Beagle dogs were administered morphine sulfate (0.5 mg/kg) as an i.v. bolus and extended release tablets were administered orally as whole tablets (1.6 ± 0.1 mg/kg) in a randomized crossover design. Plasma concentrations of morphine and M-6-G were determined using high-pressure liquid chromatography and electrochemical coulometric detection. Following i.v. administration all dogs exhibited dysphoria and sedation, and four or six dogs vomited. Mean ± SE values for half-life, apparent volume of distribution, and clearance after i.v. administration were 1.16 ± 0.15 h, 4.55 ± 0.17 L/kg, and 62.46 ± 10.44 mL/min/kg, respectively. One dog vomited following oral administration and was excluded from the oral analysis. Oral bioavailability was 5% as determined from naïve-averaged analysis. The M-6-G was not detected in any plasma samples following oral or i.v. administration of morphine at a 25 ng/mL the limit of quantification. Computer simulations concluded morphine sulfate administered 0.5 mg/kg intravenously every 2 h would maintain morphine plasma concentrations consistent with analgesic plasma concentrations in humans. Oral morphine is poorly and erratically absorbed in dogs.     

Influence of morphine sulfate on the halothane sparing effect of xylazine hydrochloride in horses

OBJECTIVE: To quantitate the dose and time-related effects of morphine sulfate on the anesthetic sparing effect of xylazine hydrochloride in halothane-anesthetized horses and determine the associated plasma xylazine and morphine concentration-time profiles. ANIMALS: 6 healthy adult horses. PROCEDURE: Horses were anesthetized 3 times to determine the minimum alveolar concentration (MAC) of halothane in O2 and characterize the anesthetic sparing effect (ie, decrease in MAC of halothane) by xylazine (0.5 mg/kg, i.v.) administration followed immediately by i.v. administration of saline (0.9% NaCI) solution, low-dose morphine (0.1 mg/kg), or high-dose morphine (0.2 mg/kg). Selected parameters of cardiopulmonary function were also determined over time to verify consistency of conditions. RESULTS: Mean (+/- SEM) MAC of halothane was 1.05 +/- 0.02% and was decreased by 20.1 +/- 6.6% at 49 +/- 2 minutes following xylazine administration. The amount of MAC reduction in response to xylazine was time dependent. Addition of morphine to xylazine administration did not contribute further to the xylazine-induced decrease in MAC (reductions of 21.9 +/- 1.2 and 20.7 +/- 1.5% at 43 +/- 4 and 40 +/- 4 minutes following xylazine-morphine treatments for low- and high-dose morphine, respectively). Overall, cardiovascular and respiratory values varied little among treatments. Kinetic parameters describing plasma concentration-time curves for xylazine were not altered by the concurrent administration of morphine. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of xylazine decreases the anesthetic requirement for halothane in horses. Concurrent morphine administration to anesthetized horses does not alter the anesthetic sparing effect of xylazine or its plasma concentration-time profile.     

Analgesic efficacy of butorphanol and morphine in bearded dragons and corn snakes

OBJECTIVE: To test the hypothesis that administration of butorphanol or morphine induces antinociception in bearded dragons and corn snakes. DESIGN: Prospective crossover study. ANIMALS: 12 juvenile and adult bearded dragons and 13 corn snakes. PROCEDURES: Infrared heat stimuli were applied to the plantar surface of bearded dragon hind limbs or the ventral surface of corn snake tails. Thermal withdrawal latencies (TWDLs) were measured before (baseline) and after SC administration of physiologic saline (0.9% NaCl) solution (equivalent volume to opioid volumes), butorphanol tartrate (2 or 20 mg/kg [0.91 or 9.1 mg/lb]), or morphine sulfate (1, 5, 10, 20, or 40 mg/kg [0.45, 2.27, 4.5, 9.1, or 18.2 mg/lb]). RESULTS: For bearded dragons, butorphanol (2 or 20 mg/kg) did not alter hind limb TWDLs at 2 to 24 hours after administration. However, at 8 hours after administration, morphine (10 and 20 mg/kg) significantly increased hind limb TWDLs from baseline values (mean +/- SEM maximum increase, 2.7+/-0.4 seconds and 2.8+/-0.9 seconds, respectively). For corn snakes, butorphanol (20 mg/kg) significantly increased tail TWDLs at 8 hours after administration (maximum increase from baseline value, 3.0+/-0.8 seconds); the low dose had no effect. Morphine injections did not increase tail TWDLs at 2 to 24 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with doses used in most mammalian species, high doses of morphine (but not butorphanol) induced analgesia in bearded dragons, whereas high doses of butorphanol (but not morphine) induced analgesia in corn snakes.     

Comparison of the effects of morphine administered by constant-rate intravenous infusion or intermittent intramuscular injection in dogs

OBJECTIVE: To compare physiologic and analgesic effects of morphine when given by IV constant-rate infusion or by IM injection to dogs undergoing laparotomy and to determine pharmacokinetics of morphine in dogs following IV constant-rate infusion. DESIGN: Prospective randomized controlled trial. ANIMALS: 20 dogs. PROCEDURE: Dogs undergoing laparotomy were treated with morphine beginning at the time of anesthetic induction. Morphine was administered by IV infusion (0.12 mg/kg/h [0.05 mg/lb/h] of body weight) or by IM injection (1 mg/kg [0.45 mg/lb]) at induction and extubation and every 4 hours thereafter. Treatments continued for 24 hours after extubation. RESULTS: Blood gas values did not indicate clinically significant respiratory depression in either group, and degree of analgesia (determined as the University of Melbourne Pain Scale score) and incidence of adverse effects (panting, vomiting, defecation, and dysphoria) were not significantly different between groups. Dogs in both groups had significant decreases in mean heart rate, rectal temperature, and serum sodium and potassium concentrations, compared with preoperative values. Mean +/- SEM total body clearance of morphine was 68 +/- 6 ml/min/kg (31 +/- 3 ml/min/lb). Mean steady-state serum morphine concentration in dogs receiving morphine by constant-rate infusion was 30 +/- 2 ng/ml. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that administration of morphine as a constant-rate IV infusion at a dose of 0.12 mg/kg/h induced effects similar to those obtained with administration at a dose of 1 mg/kg, IM, every 4 hours in dogs undergoing laparotomy. Panting was attributed to an opioid-induced resetting of the hypothalamic temperature set point, rather than respiratory depression.     

Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations.

The pharmacokinetics and bioavailability (F) of single dose sustained release morphine sulfate (OSRMS) and nonsustained release morphine sulfate (NSRMS) were compared to each other and to a bolus injection of morphine sulfate (MS) intravenously (i.v.) in dogs. Beagles (n = 6) were randomly assigned to 3 treatment groups: namely, OSRMS 15 mg orally, NSRMS 15 mg orally, and 15 mg i.v. Serum samples were drawn at intervals up to 480 min following oral and 420 min following i.v. administration. Serum was analysed for morphine concentration using a radioimmunoassay. Data were analysed using non-compartmental pharmacokinetics. The only statistically significant difference between OSRMS and NSRMS was maximum serum concentration (Cmax). There were trends toward longer time to maximum serum concentration (Tmax) and longer mean absorption time (MAT) for OSRMS when compared to NSRMS, but the differences were not statistically significant (P < 0.05). Pharmacokinetic parameters for both oral formulations exhibited large variability in the rate of absorption of MS from the gastrointestinal tract. Bioavailability of both OSRMS and NSRMS was low (15%-17%). As expected, the area under the concentration vs time curve (AUC) and Cmax for the i.v. data was significantly greater than for both oral groups, and Tmax and mean residence time (MRT) were significantly less following i.v. administration. There were no statistically significant differences among the 3 treatment groups for apparent volume of distribution at steady state (Vdss) or elimination parameters. The OSRMS formulation used in this study provided equivalent bioavailability to NSRMS in dogs, accompanied by large individual variability in drug absorption. It also did not appear that the sustained release formulation provided sufficiently prolonged release of morphine sulfate from the tablet matrix in dogs to allow prolonged dosing intervals compared to NSRMS.     

Comparison of the cardio‐respiratory effects of methadone and morphine in conscious dogs††

The effects of methadone and morphine were compared in conscious dogs. Six animals received morphine sulfate (1 mg/kg) or methadone hydrochloride (0.5 mg/kg [MET0.5] or 1.0 mg/kg [MET1.0]) intravenously (i.v.) in a randomized complete block design. Cardiopulmonary variables were recorded before (baseline), and for 120 min after drug administration. One outlier was not included in the statistical analysis for hemodynamic data. Morphine decreased heart rate (HR) compared to baseline from 30 to 120 min (?15% to ?26%), while cardiac index (CI) was reduced only at 120 min (?19%). Greater and more prolonged reductions in HR (?32% to ?46%) and in CI (?24% to ?52%) were observed after MET1.0, while intermediate reductions were recorded after MET0.5 (?19 to ?28% for HR and ?17% to ?27% for CI). The systemic vascular resistance index (SVRI) was increased after methadone; MET1.0 produced higher SVRI values than MET0.5 (maximum increases: 57% and 165% for MET0.5 and MET1.0, respectively). Compared to morphine, oxygen partial pressure (PaO₂) was lower (?12% to ?13%) at 5 min of methadone (0.5 and 1.0 mg/kg), while carbon dioxide partial pressure (PaCO₂) did not change significantly. It was concluded that methadone induces cardiovascular changes that are dose‐related and is a more potent cardiovascular depressant agent than morphine in conscious dogs.     

Pharmacokinetics and pharmacodynamics of morphine in llamas

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of morphine in llamas. ANIMALS: 6 healthy adult llamas. PROCEDURES: Llamas received morphine sulfate in a randomized crossover design. In phase 1, they received IV or IM administration of morphine at 0.05 or 0.5 mg/kg, respectively; in phase 2, they received IV administration of morphine at 0.05, 0.25, or 0.5 mg/kg. Plasma morphine and morphine-6-glucuronide concentrations were determined by validated methods. Body temperature, heart rate, respiratory rate, sedation, and analgesia were assessed and compared with plasma concentrations by regression analysis. RESULTS: Total body clearance was similar between IV administration of morphine sulfate at 0.25 and 0.5 mg/kg (mean +/- SD, 25.3 +/- 6.9 mL/min/kg and 27.3 +/- 5.9 mL/min/kg, respectively), and linearity was demonstrated between these doses. Bioavailability of morphine following IM administration at 0.5 mg/kg was 120 +/- 30%. Body temperature and sedation increased as the dose of morphine administered increased. Heart rate was unaffected by varying doses. Respiratory rate decreased as dose increased. Analgesia was difficult to assess as a result of high individual variability. Intravenous administration of morphine at 0.25 mg/kg provided the most consistent increase in tolerance to electric stimulation. Pharmacodynamic modeling revealed a sigmoidal relationship between plasma concentration and sedation score. CONCLUSIONS AND CLINICAL RELEVANCE: Morphine was characterized by a large apparent volume of distribution and high systemic clearance in llamas. A prolonged half-life was observed with IM injection. Intravenous administration of morphine sulfate at 0.25 mg/kg every 4 hours is suggested for further study.     

Effect of morphine on the bispectral index during isoflurane anesthesia in dogs

ObjectiveTo assess the effect of morphine on the bispectral index (BIS) in dogs during isoflurane anesthesia maintained at a constant end–tidal concentration.Study designProspective, randomized, experimental trial.AnimalsEight adult Beagle dogs, weighing between 7.1 and 9.8 kg.MethodsAnesthesia was induced with isoflurane via a face mask. Dog's tracheas were intubated and anesthesia maintained with isoflurane at a constant end–tidal concentration (e′Iso) of 1.81% for a 30–minute equilibration period. Pulmonary ventilation was controlled to normocapnia. After equilibration, baseline values were recorded prior to intravenous administration of morphine sulfate (0.5 mg kg^?1) (MT) or an equal volume of saline (CT). Measurements for heart rate, systolic, diastolic and mean arterial pressure (SAP, DAP and MAP) were recorded at 10, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after treatment. Bispectral index was recorded every 10 seconds for 3 minutes for each time measurement. Venous blood samples were collected at baseline, 10, 20, 30, 45, 60 and 120 minutes for determination of morphine serum concentrations. Anesthesia was discontinued after the last measurement and dogs were allowed to recover.ResultsBaseline BIS for MT and CT at 1.81%e′Iso were 63 ± 10 and 58 ± 9, respectively. Bispectral index in MT was 4–8% lower at 20, 75, 90 and 105 minutes compared with CT. There were no differences in BIS between baseline and any subsequent measurement within either MT or CT. Heart rate, SAP, MAP, and DAP decreased after morphine administration.Conclusion and clinical relevanceIntravenous administration of 0.5 mg kg^?1 morphine sulfate did not cause clinically significant changes in the BIS of unstimulated dogs during isoflurane anesthesia at an e′Iso of 1.81%.     

Effects of acetylpromazine or morphine on urine production in halothane-anesthetized dogs.

OBJECTIVE: To assess the influence of preanesthetic administration of acetylpromazine or morphine and fluids on urine production, arginine vasopressin (AVP; previously known as antidiuretic hormone) concentrations, mean arterial blood pressure (MAP), plasma osmolality (Osm), PCV, and concentration of total solids (TS) during anesthesia and surgery in dogs. ANIMALS: 19 adult dogs. PROCEDURE: Concentration of AVP, indirect MAP, Osm, PCV, and concentration of TS were measured at 5 time points (before administration of acetylpromazine or morphine, after administration of those drugs, after induction of anesthesia, 1 hour after the start of surgery, and 2 hours after the start of surgery). Urine output and end-tidal halothane concentrations were measured 1 and 2 hours after the start of surgery. All dogs were administered lactated Ringer's solution (20 ml/kg of body weight/h, i.v.) during surgery. RESULTS: Compared with values for acetylpromazine, preoperative administration of morphine resulted in significantly lower urine output during the surgical period. Groups did not differ significantly for AVP concentration, Osm, MAP, and end-tidal halothane concentration; however, PCV and concentration of TS decreased over time in both groups and were lower in dogs given acetylpromazine. CONCLUSIONS AND CLINICAL RELEVANCE: Preanesthetic administration of morphine resulted in significantly lower urine output, compared with values after administration of acetylpromazine, which cannot be explained by differences in AVP concentration or MAP When urine output is used as a guide for determining rate for i.v. administration of fluids in the perioperative period, the type of preanesthetic agent used must be considered.     

Comparison of cervical epidural morphine with intravenous morphine administration on antinociception in adult horses using thermal threshold testing

ObjectiveTo compare the antinociceptive effects of morphine administered via cervical epidural catheter to intravenously administered morphine using a thermal threshold (TT) testing model in healthy adult horses.Study designProspective, randomized, blinded experimental study.AnimalsA total of six university-owned adult horses.MethodsHorses were instrumented with a cervical (C1–C2) epidural catheter and TT testing device with probes at withers and thoracic limb coronary bands. All horses underwent three TT testing cycles including cervical epidural morphine administration (treatment EpiM; 0.1 mg kg^–1), systemic morphine administration (treatment SystM; 0.1 mg kg^–1) and no morphine administration (treatment Control). Baseline TT was established prior to treatments, and TT was tested at 15, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, 480, 600 and 720 minutes following treatment. Horses underwent a 5 day washout period between treatments and the order of treatment was randomized. Differences between treatments were analyzed with repeated measures anova.ResultsSystemic and epidural morphine administration resulted in significantly higher TT values compared with baseline and control treatment. The duration of effect was significantly longer in treatment EpiM (10–12 hours) than in treatment SystM (1.5–2.0 hours). Horses in treatment EpiM had significantly higher TT values at time points 180–600 minutes (withers) and 300–600 minutes (coronary band) than horses in treatment SystM.Conclusions and clinical relevanceCervical epidural administration of morphine provided antinociceptive effects as measured by increased TT for 10–12 hours compared with 1.5–2.0 hours for intravenously administered morphine. No complications or adverse effects were noticed following epidural placement of a C1–C2 catheter and administration of morphine. The use of a cervical epidural catheter can be considered for analgesia administration in treatment of thoracic limb and cervical pain in the horse.     

Effects of preanesthetic administration of morphine on gastroesophageal reflux and regurgitation during anesthesia in dogs

OBJECTIVE: To determine the effect of morphine administered prior to anesthesia on the incidence of gastroesophageal reflux (GER) in dogs during the subsequent anesthetic episode. ANIMALS: 90 dogs (30 dogs/group). PROCEDURE: The randomized prospective clinical study included healthy dogs with no history of vomiting. Dogs were scheduled to undergo elective orthopedic surgery. Food was withheld for (mean+/-SD) 17.8+/-4.1 hours prior to induction of anesthesia. The anesthetic protocol included acepromazine maleate, thiopental, and isoflurane. Dogs were randomly selected to receive morphine at various dosages (0, 0.22, or 1.10 mg/kg, IM) concurrent with acepromazine administration prior to induction of anesthesia. A sensor-tipped catheter was used to measure esophageal pH, and GER was defined as a decrease in pH to < 4 or an increase to > 7.5. RESULTS: 40 dogs had acidic reflux, and 1 had biliary reflux. Proportions of dogs with GER were 8 of 30 (27%), 15 of 30 (50%), and 18 of 30 (60%) for morphine dosages of 0, 0.22, and 1.10 mg/kg, respectively. Mean duration of GER was 91.4+/-56.8 minutes. There was no significant association between GER and age, weight, vomiting after preanesthetic medication, administration of antimicrobials, or start of surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Most healthy dogs vomit after a large dose of morphine, but vomiting does not increase the likelihood of GER during the subsequent anesthetic episode. Administration of morphine prior to anesthesia substantially increases the incidence of GER during the subsequent anesthetic episode.     

Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds

OBJECTIVE: To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. ANIMALS: 6 healthy Greyhounds, 3 male and 3 female. PROCEDURES: Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. RESULTS: Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. CONCLUSIONS AND CLINICAL RELEVANCE: Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.     

Postoperative analgesia in dogs receiving epidural morphine plus medetomidine

This investigation was carried out to compare the postoperative analgesia and plasma morphine concentrations in dogs given epidural morphine or epidural morphine combined with medetomidine prior to surgery. Twelve dogs (seven males and five females) with ruptured cranial cruciate ligaments presented to the Washington State University Veterinary Teaching Hospital. Six dogs received an epidural injection of morphine (0.1 mg/kg) and six dogs received epidural morphine (0.1 mg/kg) combined with medetomidine (0.005 mg/kg). Numeric rating scale (NRS) pain scores and cumulative pain scores (CPS) were assigned to 10-min segments of video. Video segments, heart rates and respiratory rates were recorded prior to premedication and at 4, 8, 12, 18 and 24 h after epidural injection. Blood was sampled from the cephalic vein at each of these times and during anesthesia at 0.5, 1, 2 and 3 h after epidural injection. Data were analyzed using either Friedman's test or one-way anova for repeated measures. In the morphine group, significant increases compared with premedication values were detected at 4, 8 and 12 h after epidural injection for NRS and at 4 and 12 h after epidural injection for CPS. In the morphine plus medetomidine group, NRS was significantly higher at 4 and 8 h whereas there were no differences from baseline values for CPS. Plasma morphine concentrations were not significantly different between treatment groups, but were significantly increased compared with preinjection values at 0.5, 1, 12, 18, and 24 h in the morphine plus medetomidine group. Epidurally administered morphine combined with medetomidine was associated with only minor benefits based on subjective pain scoring when compared with morphine alone in these dogs undergoing repair of a ruptured cranial cruciate ligament.     

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.     

Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats

This study compared pressure and thermal thresholds after administration of three opioids in eight cats. Pressure stimulation was performed via a bracelet taped around the forearm. Three ball-bearings were advanced against the forearm by inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was tested as previously reported using a heated probe held against the thorax [Dixon et al. (2002) Research in Veterinary Science, 72, 205]. After baseline recordings, each cat received subcutaneous methadone 0.2 mg/kg, morphine 0.2 mg/kg, buprenorphine 0.02 mg/kg or saline 0.3 mL in a four period cross-over study. Measurements were made at 15, 30, 45 min and 1, 2, 3, 4, 8, 12 and 24 h after the injection. Data were analysed by anova (P<0.05). There were no significant changes in thresholds after saline. Thermal threshold increased at 45 min after buprenorphine (maximum 2.8+/-3 degrees C), 1-3 h after methadone (maximum 3.4+/-1.9 degrees C) and 45 min to 1 h (maximum 3.4+/-2 degrees C) after morphine. Pressure threshold increased 30-45 min (maximum 238+/-206 mmHg) after buprenorphine, 45-60 min after methadone (maximum 255+/-232 mmHg) and 45-60 min and 3-6 h (maximum 255+/-232 mmHg) after morphine. Morphine provided the best analgesia, and methadone appears a promising alternative. Buprenorphines limited effect was probably related to the subcutaneous route of administration. Previously, buprenorphine has produced much greater effects when given by other routes.     

The effects of preoperative extradural bupivacaine and morphine on the stress response in dogs undergoing femoro-tibial joint surgery

OBJECTIVE: To evaluate the efficacy of preoperative extradural bupivacaine and morphine in attenuating the stress response in dogs undergoing femoro-tibial joint surgery. STUDY DESIGN: Prospective clinical study. Animal population Twelve client-owned dogs undergoing surgery for either repair of cruciate ligament rupture (ten) or correction of luxating patella (two). Body masses ranged from 12 to 45 kg (mean: 28.58 +/- 18.38). Age ranged from 19 to 121 months (mean: 66.5 +/- 49.5). MATERIALS AND METHODS: Six of the dogs received extradural bupivacaine (up to 1.5 mg kg(-1)) combined with morphine (0.1 mg kg(-1); ED) while the other six received no extradural analgesia (C). The levels of cortisol, acute phase proteins (APPs), and red and white blood cell variables were measured in both groups of dogs before, and at various times after surgery. Pain was also assessed at various times after surgery. The number of postoperative morphine doses required, and their time of administration, was recorded for each animal. Method of statistical analysis Data were analysed using anova for repeated measures with p-values of <0.05 considered significant. RESULTS: Cortisol levels in the ED group were significantly (p < 0.05) lower than those of the control group at the end of surgery. No statistically significant differences were found in APPs or red and white cell variables between dogs receiving, and those not receiving extradural bupivacaine and morphine. Four dogs in the control group and one in the ED group required postoperative morphine. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-emptive extradural bupivacaine and morphine was effective in lowering the neuroendocrine stress response (cortisol) in the ED group but had no effect on the inflammatory response (acute phase response).     

Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats

This study describes the pharmacokinetics of intravenous hydromorphone in cats and the simultaneous measurement of antinociceptive pharmacodynamic effects using a thermal threshold testing system. Following establishment of a baseline thermal threshold, six adult cats were administered 0.1 mg/kg of hydromorphone intravenously. Thermal threshold testing and blood collection were conducted simultaneously at predetermined time points. Plasma hydromorphone concentrations were determined by a liquid chromatographic-mass spectral method and pharmacokinetic analysis was performed by nonlinear least squares regression analysis. Plasma hydromorphone concentrations declined rapidly over time, and were below the limit of quantification of the assay (LOQ = 1.0 ng/mL) by 360 min. In contrast, thermal thresholds rose from a pretreatment value of 40.9 +/- 0.65 degrees C (mean +/- SEM) to instrument cut-out (55 degrees C) within 15 min and remained significantly elevated from 15-450 min after treatment. Inspection of the data revealed no direct correlation between plasma hydromorphone concentrations and the antinociceptive effect of this drug in cats. These findings support the importance of conducting pharmacokinetic studies in parallel with objective measurements of drug effect.