Epidural anesthesia with bupivacaine, bupivacaine and fentanyl, or bupivacaine and sufentanil during intravenous administration of propofol for ovariohysterectomy in dogs

OBJECTIVE: To compare cardiovascular and systemic effects and analgesia during the postoperative period of epidural anesthesia performed with bupivacaine alone or with fentanyl or sufentanil in bitches maintained at a light plane of anesthesia with continuous infusion of propofol. STUDY DESIGN: Prospective randomized masked clinical trial. ANIMALS: 30 female dogs of various breeds. PROCEDURES: Dogs were allocated into 3 groups of 10 each. One group received fentanyl (2 microg/kg [0.91 microg/lb]) and bupivacaine (1 mg/kg [0.45 mg/lb]), 1 group received sufentanil (1 microg/kg) and bupivacaine (1 mg/kg), and 1 group received bupivacaine (1 mg/kg). All dogs received acepromazine (0.1 mg/kg [0.045 mg/lb]) and continuous infusion of propofol for sedation. The agents were administered into the lumbosacral space and diluted in saline (0.9% NaCl) solution to a total volume of 0.36 mL/kg (0.164 mL/lb). Cardiac and respiratory rates, arterial blood pressures, pH, and blood gases were evaluated. Analgesia, sedation level, serum cortisol concentrations, and plasma catecholamine concentrations were measured regularly for 6 hours. RESULTS: No important changes in cardiovascular, respiratory, or sedation variables were observed. Degree of analgesia in the postoperative period was higher in the sufentanil group, although use of fentanyl and bupivacaine also resulted in a sufficient level of analgesia. CONCLUSIONS AND CLINICAL RELEVANCE: Use of the 3 anesthetic techniques permitted ovariohysterectomy with sufficient analgesia and acceptable neuroendocrine modulation of pain with minimal adverse effects.     

Epidural anaesthesia using lignocaine, bupivacaine or a mixture of lignocaine and bupivacaine in dogs

The time to loss of interdigital reflex, duration of action, duration of muscle relaxation and cardiorespiratory effects were compared after epidural block using lignocaine, bupivacaine or a combination of lignocaine and bupivacaine in dogs. Dogs were pre-medicated with methotrimeprazine, anaesthesia was induced with thiopentone, in order to facilitate epidural puncture, and a lumbosacral epidural block was performed. Body temperature fell after pre-medication, thiopentone and epidural anaesthesia. Minimal changes were observed in arterial O₂ saturation, end tidal CO₂, respiratory rate, heart rate and mean arterial blood pressure. The combination of bupivacaine with lignocaine produced a shorter time to loss of interdigital reflex than bupivacaine alone, longer analgesia than lignocaine alone and longer muscle relaxation than either lignocaine or bupivacaine. The combination appeared to be the best choice when surgical time is prolonged.     

Bioavailability of morphine,methadone, hydromorphone,and oxymorphone following buccal administration in cats

Buccal administration of buprenorphine is commonly used to treat pain in cats. It has been argued that absorption of buprenorphine through the buccal mucosa is high, in part due to its pKa of 8.24. Morphine, methadone, hydromorphone, and oxymorphone have a pKa between 8 and 9. This study characterized the bioavailability of these drugs following buccal administration to cats. Six healthy adult female spayed cats were used. Buccal pH was measured prior to drug administration. Morphine sulfate, 0.2 mg/kg IV or 0.5 mg/kg buccal; methadone hydrochloride, 0.3 mg/kg IV or 0.75 mg/kg buccal; hydromorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal; or oxymorphone hydrochloride, 0.1 mg/kg IV or 0.25 mg/kg buccal were administered. All cats received all treatments. Arterial blood was sampled immediately prior to drug administration and at various times up to 8 h thereafter. Bioavailability was calculated as the ratio of the area under the time–concentration curve following buccal administration to that following IV administration, each indexed to the administered dose. Mean ± SE (range) bioavailability was 36.6 ± 5.2 (12.7–49.5), 44.2 ± 7.9 (18.7–70.5), 22.4 ± 6.9 (6.4–43.4), and 18.8 ± 2.0 (12.9–23.5)% for buccal administration of morphine, methadone, hydromorphone, and oxymorphone, respectively. Bioavailability of methadone was significantly higher than that of oxymorphone.     

Clinical pharmacology of methadone in dogs

ObjectiveTo investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs.Study designRandomized, cross-over, experimental trial.AnimalsNine adult dogs (beagle and beagle cross breeds), four males and five females.MethodsMethadone hydrochloride, 0.4 mg kg^?1, was administered intravenously (IV) and subcutaneously (SC) with a crossover design. Drug and hormone analyses in plasma were performed using Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry and radioimmunoassay respectively. Behavioural data were collected using a standardized protocol.ResultsAfter IV administration, the plasma concentration of methadone at 10 minutes was 82.1 ± 9.2 ng mL^?1 (mean ± SD), the terminal half-life was 3.9 ± 1.0 hours, the volume of distribution 9.2 ± 3.3 L kg^?1 and plasma clearance 27.9 ± 7.6 mL minute^?1 kg^?1. After SC administration, time to maximal plasma concentration was 1.26 ± 1.04 hours and maximal plasma concentration of methadone was 23.9 ± 14.4 ng mL^?1, the terminal half-life was 10.7 ± 4.3 hours and bioavailability was 79 ± 22%. Concentrations of both cortisol and vasopressin were increased for an hour following IV methadone. The observed behavioural effects of methadone were decreased licking and swallowing and an increase in whining after SC administration. The latter finding is notable as it can be misinterpreted as pain when methadone is used as an analgesic.Conclusion and clinical relevanceWhen methadone was administered by the SC route, the half-life was longer, but the individual variation in plasma concentrations was greater compared with IV administration. Increased frequency of whining occurred after administration of methadone and may be a drug effect and not a sign of pain. Cortisol and vasopressin concentrations in plasma may not be suitable for evaluating analgesia after methadone treatment.     

Neurotoxicity of intraneural injection of bupivacaine liposome injectable suspension versus bupivacaine hydrochloride in a porcine model

Objective

To test whether neurotoxic effects of a bupivacaine liposome injectable suspension differ from those of a standard formulation of bupivacaine hydrochloride (HCl) after intraneural injection into the sciatic nerves in pigs.

Comparison of the cytotoxic effects of bupivacaine, lidocaine, and mepivacaine in equine articular chondrocytes

Objective To compare the chondrotoxicity of bupivacaine, lidocaine, and mepivacaine in equine articular chondrocytes in vitro. Study design Prospective, experimental study. Study material Equine articular chondrocytes. Methods Primary cultured equine chondrocytes were exposed to 0.5% bupivacaine, 2% lidocaine, or 2% mepivacaine for 30 or 60 minutes. After treatment, cell viability was evaluated by trypan blue exclusion and the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) colorimetric assay in a dose dependent manner. Apoptosis and necrosis of chondrocytes were analyzed with the double staining of Hoechst 33258 and propidium iodide using fluorescence microscopy, and the results were confirmed using flow cytometry. Results After 30‐minute exposure, trypan blue exclusion assay revealed that cell viability of 0.5% bupivacaine group was 28.73 ± 8.44%, and those of 2% lidocaine and 2% mepivacaine were 66.85 ± 6.03% and 86.27 ± 2.00%, respectively. The viability of chondrocytes after saline treatment was 95.95 ± 2.75%. The results of MTT assay and fluorescence microscopy had similar tendency with trypan blue assay. Each result showed that bupivacaine was the most toxic of the three local anaesthetics. Mepivacaine was less toxic than lidocaine. The results of the viability test suggest that bupivacaine and lidocaine exhibit a marked chondrotoxicity, and that this is mainly due to necrosis rather than apoptosis. Conclusions and clinical relevance Bupivacaine may induce detrimental chondrotoxicity when administered intra‐articularly, especially in patients with joint disease, and we suggest that it should be used cautiously in equine practice. Mepivacaine may be an alternative to both bupivacaine and lidocaine.     

Estimated plasma bupivacaine concentration after single dose and eight-hour continuous intra-articular infusion of bupivacaine in normal dogs

Objective— To estimate maximum plasma concentration (C_max) and time to maximum plasma (t_max) bupivacaine concentration after intra‐articular administration of bupivacaine for single injection (SI) and injection followed by continuous infusion (CI) in normal dogs. Study Design— Cross‐over design with a 2‐week washout period. Animals— Healthy Coon Hound dogs (n=8). Methods— Using gas chromatography/mass spectrometry, canine plasma bupivacaine concentration was measured before and after SI (1.5 mg/kg) and CI (1.5 mg/kg and 0.3 mg/kg/h). Software was used to establish plasma concentration–time curves and estimate C_max, T_max and other pharmacokinetic variables for comparison of SI and CI. Results— Bupivacaine plasma concentration after SI and CI best fit a 3 exponential model. For SI, mean maximum concentration (C_max, 1.33±0.954 μg/mL) occurred at 11.37±4.546 minutes. For CI, mean C_max (1.13±0.509 μg/mL) occurred at 10.37±4.109 minutes. The area under the concentration–time curve was smaller for SI (143.59±118.390 μg/mL × min) than for CI (626.502±423.653 μg/mL × min, P=.02) and half‐life was shorter for SI (61.33±77.706 minutes) than for CI (245.363±104.415 minutes, P=.01). The highest plasma bupivacaine concentration for any dog was 3.2 μg/mL for SI and 2.3 μg/mL for CI. Conclusion— Intra‐articular bupivacaine administration results in delayed absorption from the stifle into the systemic circulation with mean C_max below that considered toxic and no systemic drug accumulation. Clinical Relevance— Intra‐articular bupivacaine can be administered with small risk of reaching toxic plasma concentrations in dogs, though toxic concentrations may be approached. Caution should be exercised with multimodal bupivacaine administration because plasma drug concentration may rise higher than with single intra‐articular injection.     

Comparison of bupivacaine femoral and sciatic nerve block versus bupivacaine and morphine epidural for stifle surgery in dogs

ObjectiveTo evaluate the efficacy of combined femoral and sciatic nerve blocks as an alternative to epidural anesthesia and analgesia in dogs undergoing stifle surgery under general anesthesia.Study designProspective, blinded, randomized, clinical comparison.AnimalsTwenty dogs weighing 37 ± 11 (mean ± SD) kg, aged 3 (1–8) [median (minimum–maximum)] years undergoing elective unilateral tibial-plateau leveling osteotomy.MethodsDogs were assigned randomly to receive either epidural anesthesia (bupivacaine 0.5%, 0.5 mg kg^?1 + morphine 0.1%, 0.1 mg kg^?1, in 0.2 mL kg^?1; EPID) or femoral and sciatic nerve blocks (Bupivacaine 0.5%, 0.1 mL kg^?1, was administered at each site; F + S) guided by electrolocation. All patients received a standard general anesthesia technique. Pain and sedation were scored (on scales of 0–10 and 0–3, respectively) pre-operatively, at extubation, and at 1, 4 and then every 4 hours thereafter up to 24 hours. Postoperatively, hydromorphone was administered to any patient with a pain score of >5 or whenever the blinded caregiver determined that more hydromorphone was necessary. Intraoperative heart rate (HR), mean arterial pressure (MAP), end tidal isoflurane (FE′ISO), body temperature, post-operative pain scores, time to first hydromorphone dose after surgery, time to first feeding, time to first drinking, time to first urination, time to first ambulation (walk on a lead) and cumulative dose of hydromorphone were recorded.ResultsIntra-operatively, FE′ISO and MAP were significantly lower in the EPID group (p = 0.05 and p = 0.04, respectively). Postoperatively, the cumulative hydromorphone consumption (p = 0.04) and the incidence of urinary retention (p = 0.03) were higher in the EPID group.Conclusion and clinical relevance F + S is a practical alternative to EPID that produces less urine retention and reduces opioid consumption in the 24 hours after surgery. EPID might be associated with a lower isoflurane requirement and lower systemic blood pressure.     

Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses

We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated‐measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed‐rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC‐MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd_ss/F) and increased mean residence time (MRT) for NANO. One‐compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone.     

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.     

Effects of medetomidine,l‐methadone,and their combination on arterial blood gases in dogs

ObjectiveTo investigate the influence of l–methadone on medetomidine–induced changes in arterial blood gases and clinical sedation in dogs.Study designProspective experimental cross–over study (Latin square design).AnimalsFive 1–year–old purpose bred laboratory beagle dogs of both sexes.MethodsEach dog was treated three times: medetomidine (20 μg kg^?1 IV), l–methadone (0.1 mg kg^?1 IV) and their combination. Arterial blood was collected for blood gas analysis. Heart and respiratory rates were recorded, and clinical sedation and reaction to a painful stimulus were scored before drug administration and at various time points for 30 minutes thereafter.ResultsArterial partial pressure of oxygen decreased slightly after medetomidine administration and further after medetomidine/l–methadone administration (range 55.2–86.7 mmHg, 7.4–11.6 kPa, at 5 minutes). A slight increase was detected in arterial partial pressure of carbon dioxide after administration of l–methadone and medetomidine/l–methadone (42.6 ± 2.9 and 44.7 ± 2.4 mmHg, 5.7 ± 0.4 and 6.0 ± 0.3 kPa, 30 minutes after drug administration, respectively). Arterial pH decreased slightly after administration of l–methadone and medetomidine/l–methadone. Heart and respiratory rates decreased after administration of medetomidine and medetomidine/l–methadone, and no differences were detected between the two treatments. Most dogs panted after administration of l–methadone and there was slight sedation. Medetomidine induced moderate or deep sedation, and all dogs were deeply sedated after administration of medetomidine/l–methadone. Reaction to a noxious stimulus was strong or moderate after administration of methadone, moderate or absent after administration of medetomidine, and absent after administration of medetomidine/l–methadone.Conclusions and clinical relevanceAt the doses used in this study, l–methadone potentiated the sedative and analgesic effects and the decrease in arterial oxygenation induced by medetomidine in dogs, which limits the clinical use of this combination.     

Comparative study on the sedative effects of morphine, methadone, butorphanol or tramadol, in combination with acepromazine, in dogs

Objective  To compare the effects of morphine (MOR), methadone (MET), butorphanol (BUT) and tramadol (TRA), in combination with acepromazine, on sedation, cardiorespiratory variables, body temperature and incidence of emesis in dogs.
Study design  Prospective randomized, blinded, experimental trial.
Animals  Six adult mixed-breed male dogs weighing 12.0 ± 4.3 kg.
Methods  Dogs received intravenous administration (IV) of acepromazine (0.05 mg kg⁻¹) and 15 minutes later, one of four opioids was randomly administered IV in a cross-over design, with at least 1-week intervals. Dogs then received MOR 0.5 mg kg⁻¹; MET 0.5 mg kg⁻¹; BUT 0.15 mg kg⁻¹; or TRA 2.0 mg kg⁻¹. Indirect systolic arterial pressure (SAP), heart rate (HR), respiratory rate ( f _R), rectal temperature, pedal withdrawal reflex and sedation were evaluated at regular intervals for 90 minutes.
Results  Acepromazine administration decreased SAP, HR and temperature and produced mild sedation. All opioids further decreased temperature and MOR, BUT and TRA were associated with further decreases in HR. Tramadol decreased SAP whereas BUT decreased f _R compared with values before opioid administration. Retching was observed in five of six dogs and vomiting occurred in one dog in MOR, but not in any dog in the remaining treatments. Sedation scores were greater in MET followed by MOR and BUT. Tramadol was associated with minor changes in sedation produced by acepromazine alone.
Conclusions and clinical relevance  When used with acepromazine, MET appears to provide better sedation than MOR, BUT and TRA. If vomiting is to be avoided, MET, BUT and TRA may be better options than MOR.