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.     

Cardiorespiratory,sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone,morphine or tramadol in dogs

ObjectiveTo evaluate the cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone, morphine or tramadol in dogs.Study designExperimental, blinded, randomized, crossover study.AnimalsSix mixed breed dogs (two males and four females) weighing 10 ± 4 kg.MethodsThe animals were randomly divided into four treatments: D (10 μg kg^?1 of dexmedetomidine), DM (dexmedetomidine 10 μg kg^?1 and methadone 0.5 mg kg^?1); DMO (dexmedetomidine 10 μg kg^?1 and morphine 0.5 mg kg^?1), and DT (dexmedetomidine 10 μg kg^?1 and tramadol 2 mg kg^?1). The combinations were administered intramuscularly in all treatments. The variables evaluated were heart rate (HR), respiratory rate (f_R), rectal temperature (RT), systolic arterial pressure (SAP), sedation scale and pedal withdrawal reflex. These variables were measured at T0 (immediately before the administration of the protocol) and every 15 minutes thereafter until T105.ResultsA decrease in HR and f_R occurred in all the treatments compared with T0, but no significant difference was observed between the treatments. The RT decreased from T45 onward in all the treatments. The SAP did not show a difference between the treatments, but in the DT treatment, the SAP was lower at T30 and T45 compared with T0. The D treatment had lower scores of sedation at T15 to T75 compared with the other treatments, and the DMO and DM treatments showed higher scores at T60 and T75 compared with DT.Conclusions and clinical relevanceThe treatments with morphine and methadone added to the dexmedetomidine showed higher sedation scores than the control treatment and the treatment with tramadol added to the dexmedetomidine showed no relevant differences in any of the variables evaluated in the study.     

Quantitative sensory testing with Electronic von Frey Anesthesiometer and von Frey filaments in nonpainful cats: a pilot study

Objective

Measurement of sensory thresholds could represent a complementary tool to behavioural pain scores in cats. The aim of this study was to investigate the feasibility of quantitative sensory testing (QST) with the Electronic von Frey Anesthesiometer (EVF) and von Frey filaments (VFF) in healthy cats, and to assess the limits of agreement (LOA) between the two devices.

Assessment of the respiratory actions of intramuscular morphine in conscious dogs.

The actions on the respiratory system of 0.25, 0.5 and 1.0 mg kg(-1) morphine given intramuscularly were studied in conscious dogs. Dogs breathed oxygen with 0, 2 and 4 per cent CO(2), in that order, through a mask attached to a flow sensor and connected to a respiratory mechanics monitor. When a steady state period of respiration was reached breathing pure oxygen, respiratory rate, tidal volume, respiratory minute volume, peak expiratory flow rate and end tidal CO(2)(PetCO(2)) were measured. The respiratory minute volume and PetCO(2) were measured when the dogs breathed 2 and 4 per cent CO(2) in oxygen, the points plotted onto a graph and the gradient of the line, describing the PCO(2)/ventilation response, plus the intercept with the y-axis were determined. Measurements for each morphine dose were taken before injection and at 30 minutes, 1, 2, 3, 4, 6 and 8 hours post injection.The incidence of panting after morphine was dose related and it occurred in all dogs given the high dose. Morphine reduced the gradients of the PCO(2)/ventilation response lines and raised the intercept. Other changes were increased respiratory minute volume and peak expiratory flow and decreased PetCO(2) and tidal volume.     

Comparison of behavioral effects of morphine and fentanyl in dogs and cats

Behavioral effects induced by intravenous administration of morphine at 0.3, 0.6, 1.2, and 2.4 μg/kg and fentanyl at 5, 10, 20, and 40 μg/kg were evaluated in dogs and cats. In dogs, fentanyl and morphine depressed activity and level of consciousness in a dose- dependant manner. In cats, higher doses of fentanyl stimulated activity temporarily, but excitement, so-called "opioid mania," was not observed. Morphine induced distinctive behavioral changes characterized by sitting with fixed staring, and "opioid mania" was not observed in cats.     

Assessment of ultrasonography and computed tomography for the evaluation of unilateral orbital disease in dogs

OBJECTIVE: To describe clinical, ultrasonographic, and computed tomographic (CT) features of confirmed neoplastic and nonneoplastic disease in dogs with unilateral orbital diseases, determine criteria to differentiate between the 2 conditions, and assess the relative value of ultrasonography and CT for the differential diagnosis of these 2 conditions. DESIGN: Prospective study. ANIMALS: 29 dogs with unilateral neoplastic orbital disease and 16 dogs with unilateral nonneoplastic orbital disease. PROCEDURES: Clinical history and results of physical and ophthalmologic examinations were recorded. Ultrasonographic and CT images were evaluated, and discriminating factors were identified to differentiate neoplastic from nonneoplastic diseases. Diagnostic value of ultrasonography and CT was assessed. RESULTS: Dogs with neoplastic disease were significantly older; had clinical signs for a longer time before initial examination; had more progressive onset of clinical signs; and more frequently had protrusion of the nictitating membrane, fever, and anorexia. The most discriminating factor for both imaging modalities was delineation of the margins (odds ratio was 41.7 for ultrasonography and 45 for CT), with neoplastic lesions clearly delineated more often. Ultrasonographically, neoplastic lesions were more frequently hypoechoic and homogeneous, with indentation of the globe and bone involvement evident more frequently than for nonneoplastic lesions. Mineralization was detected only with neoplasia. Fluctuant fluid was seen more frequently in dogs with nonneoplastic disease. Computed tomography more frequently revealed extraorbital involvement. Diagnostic value was similar for both imaging modalities. CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonography and CT are valuable imaging modalities to assist in differentiating neoplastic from nonneoplastic unilateral orbital disease in dogs.     

Cardiopulmonary effects of a new inspiratory impedance threshold device in anesthetized hypotensive dogs

ObjectiveTo compare the hemodynamic and respiratory effects of an inspiratory impedance threshold device (ITD) in anesthetized normotensive and hypotensive dogs.Study designProspective randomized study.AnimalsTen adult dogs.MethodsDogs were anesthetized with propofol followed by isoflurane. During spontaneous ventilation, tidal volume ( $\dot{\mathrm{V}}$), systolic (SAP), mean (MAP) and diastolic arterial blood pressure, central venous pressure, gastric PCO₂ as an indicator of gastric perfusion, subcutaneous oxygen tension, subcutaneous blood flow, cardiac index (CI), systemic vascular resistance and blood lactate were monitored. To monitor respiratory compliance (RC) and resistance (ResR), animals were briefly placed on mechanical ventilation. Dogs were studied under four different conditions: 1) normotension (MAP > 60 mmHg) with and without the ITD and 2) hypotension (target MAP = 40 mmHg) with and without ITD. These four conditions were performed during one anesthetic period, allowing for stabilization of parameters for each condition. Data were analyzed by anova repeated measure mixed models.ResultsNo cardiovascular changes were detected between no ITD and ITD in the normotensive state. During hypotension, CI was higher with the ITD (5 ± 1.0 L minute^?1 m^?2) compared with no ITD (4 ± 1.3 L minute^?1 m^?2). During hypotension, SAP was increased with ITD (80 ± 14 mmHg) versus without ITD (67 ± 13 mmHg). There was an increase in ResR and decreased RC with the ITD in both normotensive and hypotensive state.Conclusion and clinical relevanceImpedance threshold device in dogs during isoflurane-induced hypotension improved CI and SAP but had negative effects on RC and ResR.     

The dose–response relation for the antinociceptive effect of morphine in a fish,rainbow trout

Jones, S. G., Kamunde, C., Lemke, K., Stevens, E. D. The dose–response relation for the antinociceptive effect of morphine in a fish, rainbow trout. J. vet. Pharmacol. Therap.  35 , 563–570. There have been suggestions that analgesics be used by fish researchers. But in the absence of dose–response data for morphine, this suggestion seems imprudent. The purpose of the present study was to develop a dose–response relationship in fish using six doses of morphine. The response (movement of the fins or tail) to a noxious stimulus (electrical shock to the face region) was monitored before and after a dose of morphine intraperitoneally (i.p.). The i.p. dose of morphine ED₅₀ in rainbow trout was 6.7 ± 0.8 mg/kg (n = 12 at each dose). The plasma morphine concentration EC₅₀ was 4.1 ± 1.5 mg/L. In a second experiment, rainbow trout tested with equal amounts of morphine and naloxone (30 mg/kg) showed that the antinociceptive effect of morphine was blocked by naloxone. It has been suggested that stress‐induced analgesia has been a confounding factor in some fish studies. However, plasma cortisol levels in our study indicated that stress was not a confounding factor in the present experiments. The ED₅₀ for morphine in fish was higher than that reported for humans or other mammals. Our observation showing a dose–response relation for morphine using a noxious stimulus supports arguments for its effectiveness as an antinociceptive drug in fish.     

Echocardiographic evaluation of the effects of medetomidine and xylazine in dogs

The echocardiographic effects of medetomidine and xylazine were evaluated in 6 healthy dogs. Values for echocardiographic variables were significantly different from pre-treatment values after administration of both drugs. The effects of medetomidine were similar to that of xylazine. Because of their cardiac depressant effects, both drugs should be used with care in sick dogs.     

An evaluation of the analgesic effects of meloxicam in addition to epidural morphine/mepivacaine in dogs undergoing cranial cruciate ligament repair

The analgesic efficacy of an epidural morphine/mepivacaine combination alone versus epidural morphine/mepivacaine in combination with meloxicam administered prior to the onset of anesthesia was assessed in 20 dogs undergoing cranial cruciate ligament repair. Numerical and visual analog pain scores were performed prior to anesthesia and at 6, 8, 12, 16, and 24 hours after epidural administration by a trained observer, blinded to treatment. An analgesiometer was used to determine the amount of pressure required to produce an avoidance response at the incision site. Animals that received meloxicam demonstrated a trend toward decreased pain scores over all time periods. Visual analog pain scores tended to be lower in dogs receiving meloxicam across all time periods, with a significant interaction between time and visual analog score at 6 and 8 hours (P < 0.05). No dogs receiving meloxicam required rescue analgesia, while 3 of 10 dogs in the epidural only group required rescue analgesia. Administration of meloxicam in addition to epidural morphine plus mepivacaine conveys improved analgesia as compared with epidural alone. Postoperative analgesia is reliably maintained for 24 hours following administration.     

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.     

Use of a vessel sealant device for splenectomy in dogs

Objective: To (1) describe a technique for splenic vessel hemostasis and (2) report complications and outcome after use of bipolar sealant device during splenectomy in dogs. Study Design: Case series. Animals: Dogs (n=27) with naturally occurring splenic disease. Methods: Between January 2006 and March 2008, splenectomy was performed using a vessel sealant device in 27 dogs with naturally occurring splenic disease. Number of sutures needed for splenectomy and complications were recorded. Splenic artery diameter was measured using a caliper. Intraoperative hemostasis, device ease of use, postoperative hemorrhage, and short‐term survival were evaluated. Results: Splenectomy was performed successfully in 27 dogs with the vessel sealant device; none of the dogs required vessel ligation with suture. The splenic artery was dissected and adequately sealed in each dog. One dog was readmitted 4 days after surgery with hemoabdomen. Abdominal exploration revealed splenic pedicle hemorrhage and pancreatitis, the vessel sealant device was used to coagulate splenic pedicle bleeding. The dog was alive at suture removal. Conclusion: In dogs, a vessel sealant device may be used to achieve efficient and safe hemostasis of the splenic vascular pedicle without sutures.     

Pharmacokinetics and physiological effects of two intravenous infusion rates of morphine in conscious dogs

This study examined the pharmacokinetics and physiologic effects of two infusions rates of morphine in conscious dogs. Five adult dogs were randomly studied at weekly intervals. An initial dose of either 0.3 or 0.6 mg/kg were each followed by infusions of 0.17 and 0.34 mg/kg/h. Plasma morphine concentrations, physiological parameters, sedation and mechanical antinociception were evaluated during each infusion. Morphine was assayed by high pressure liquid chromatography (HPLC) with electrochemical coulometric detection and pharmacokinetic parameters were calculated. Data were fitted to a bi-compartment model with a rapid distribution (<1 min for both doses) and slower termination rate. For the high and low doses, respectively, mean+/-SD terminal half-life was 38+/-5 and 27+/-14 min, apparent volumes of distribution at steady-state were 1.9+/-0.5 and 1.3+/-0.8 L/kg, with clearances of 50+/-15 and 67+/-20 mL/kg/min. Steady-state plasma concentrations ranged from 93 to 180 ng/mL and 45 to 80 ng/mL in the high and low doses, respectively. Respiratory rate increased significantly, pulse oximetry remained>95% and body temperature decreased significantly during both infusions. No vomition or neuroexcitation occurred. Sedation and mechanical antinociception were both mild during the lower infusion rate, and mild to moderate during the higher infusion rate. In conclusion, morphine pharmacokinetics was not altered by increasing infusion rates, producing stable, long-lasting plasma concentrations.     

Comparison of clinical effects of epidural levobupivacaine morphine versus bupivacaine morphine in dogs undergoing elective pelvic limb surgery

Objective

To evaluate the efficacy, in terms of the amount of rescue analgesia required, and the clinical usefulness of epidural injection of morphine with bupivacaine or levobupivacaine for elective pelvic limb surgery in dogs during a 24-hour perioperative period.

Cardiorespiratory effects of epidural administration of morphine and fentanyl in dogs anesthetized with sevoflurane

OBJECTIVE: To determine the cardiorespiratory effects of epidural administration of morphine alone and in combination with fentanyl in dogs anesthetized with sevoflurane. DESIGN: Prospective study. ANIMALS: 6 dogs. PROCEDURE: Dogs were anesthetized with sevoflurane and allowed to breathe spontaneously. After a stable plane of anesthesia was achieved, morphine (0.1 mg/kg [0.045 mg/lb]) or a combination of morphine and fentanyl (10 microg/kg [4.5 microg/lb]) was administered through an epidural catheter, the tip of which was positioned at the level of L6 or L7. Cardiorespiratory variables were measured for 90 minutes. RESULTS: Epidural administration of morphine alone did not cause any significant changes in cardiorespiratory measurements. However, epidural administration of morphine and fentanyl induced significant decreases in diastolic and mean arterial blood pressures and total peripheral resistance. Stroke volume was unchanged, PaCO2 was significantly increased, and arterial pH and base excess were significantly decreased. Heart rate was significantly lower after epidural administration of morphine and fentanyl than after administration of morphine alone. None of the dogs had any evidence of urine retention, vomiting, or pruritus after recovery from anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that epidural administration of morphine at a dose of 0.1 mg/kg in combination with fentanyl at a dose of 10 microg/kg can cause cardiorespiratory depression in dogs anesthetized with sevoflurane.