Pharmacokinetics of intramuscular L-carvone in sheep.

OBJECTIVE: To measure and model concentrations of the analgesic L-carvone, a natural component of spearmint, over time when administered IM to sheep and to characterize L-carvone's effects on CBCs and clinical biochemistry panels. METHODS: L-carvone formulated as a 50% solution (v/v) in ethanol and propylene glycol was administered at 71.6 mg/kg IM, split between each semitendinosus muscle in 6 sheep. Venous blood was sampled over 24 hours, and plasma was separated by centrifugation. Additional blood was collected for CBC and serum biochemical analysis, and tissues were sampled after euthanasia. L-carvone concentrations in plasma and tissue homogenates were measured using HPLC-MS-MS. Plasma pharmacokinetic data were described using a nonlinear mixed effects model. Complete blood count and biochemistry data were compared to baseline values using repeated-measures ANOVA and Holm-Sidák tests (P < .05). RESULTS: Maximum plasma concentrations ranged from 0.28 to 1.93 µg/mL and occurred within 9 to 15 minutes after injection. Pharmacokinetics were best described using 2 compartments. Elimination half-life was 33.7 minutes and 390.2 minutes in the central and peripheral compartments, respectively. Mild increases in neutrophil count and significant increases in creatinine kinase and aspartate aminotransferase were associated with injection site myonecrosis. No physical examination, behavioral, or other clinically significant laboratory changes were noted. CONCLUSIONS: Intramuscular L-carvone exhibits rapid time to peak concentration, relatively slow plasma elimination, and low tissue concentrations after 24 hours. CLINICAL RELEVANCE: L-carvone exhibits a favorable pharmacokinetic profile for an analgesic drug. A new L-carvone formulation or administration route is needed to reduce inflammation and necrosis at the injection site.

Ultrasound-guided trigeminal nerve approach at the level of the pterygopalatine fossa in cat cadavers.

OBJECTIVE: To describe an ultrasound-guided suprazygomatic approach to the trigeminal nerve block in cat cadavers. STUDY DESIGN: Prospective descriptive study. ANIMALS: Ten feline cadaver heads. METHODS: A 25:75 methylene blue-iopamidol mixture (0.1 mL cm-1 cranium length) was injected into 10 cadaver heads using an ultrasound-guided suprazygomatic approach. A computed tomography (CT) scan was performed to identify contrast presence at the orbital fissure, foramen rotundum and ovale, followed by anatomical dissection to identify staining of the pterygopalatine fossa (PPF), extraconal retrobulbar area, mandibular and maxillary nerves. Descriptive statistics were used to summarize results. RESULTS: A total of 20 injections were performed. Of these, 1/20 misinjection occurred and excluded from further reporting. The volume of injectate was 0.9 (0.9-1.1) mL [median (range)]. Staining of the PPF, extraconal space, maxillary and mandibular nerves over more than 6 mm was achieved in 19/19 (100%), 18/19 (95%), 17/19 (89%) and 19/19 (100%) of injections, respectively. CT showed presence of contrast within 5 mm of the orbital fissure, foramen rotundum and ovale in 18/19 (95%), 19/19 (100%) and 19/19 (100%) of the injections, respectively. No intracranial migration was observed. CONCLUSIONS AND CLINICAL RELEVANCE: This cadaver study illustrates that the suprazygomatic ultrasound-guided trigeminal nerve injection technique can successfully stain the PPF, retrobulbar cone extraconally, mandibular and maxillary nerves. Consequently, this technique has the potential to be used in vivo in cats to desensitize areas innervated by the trigeminal nerve.

Effects of trazodone and dexmedetomidine on fentanyl-mediated reduction of isoflurane minimum alveolar concentration in cats.

OBJECTIVE: To screen modulators of biogenic amine (BA) neurotransmission for the ability to cause fentanyl to decrease isoflurane minimum alveolar concentration (MAC) in cats, and to test whether fentanyl plus a combination of modulators decreases isoflurane MAC more than fentanyl alone. STUDY DESIGN: Prospective, experimental study. ANIMALS: A total of six adult male Domestic Short Hair cats. METHODS: Each cat was anesthetized in three phases with a 1 week washout between studies. In phase 1, anesthesia was induced and maintained with isoflurane, and MAC was measured in duplicate using a tail clamp stimulus and standard bracketing technique. A 21 ng mL-1 fentanyl target-controlled infusion was then administered and MAC measured again. In phase 2, a single cat was administered a single BA modulator (buspirone, haloperidol, dexmedetomidine, pregabalin, ramelteon or trazodone) in a pilot drug screen, and isoflurane MAC was measured before and after fentanyl administration. In phase 3, isoflurane MAC was measured before and after fentanyl administration in cats co-administered trazodone and dexmedetomidine, the two BA modulator drugs associated with fentanyl MAC-sparing in the screen. Isoflurane MAC-sparing by fentanyl alone, trazodone-dexmedetomidine and trazodone-dexmedetomidine-fentanyl was evaluated using paired t tests with p < 0.05 denoting significant effects. RESULTS: The MAC of isoflurane was 1.87% ± 0.09 and was not significantly affected by fentanyl administration (p = 0.09). In the BA screen, cats administered trazodone or dexmedetomidine exhibited 26% and 22% fentanyl MAC-sparing, respectively. Trazodone-dexmedetomidine co-administration decreased isoflurane MAC to 1.50% ± 0.14 (p < 0.001), and the addition of fentanyl further decreased MAC to 0.95% ± 0.16 (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl alone does not affect isoflurane MAC in cats, but co-administration of trazodone and dexmedetomidine causes fentanyl to significantly decrease isoflurane requirement.

Pregabalin produces similar effects as gabapentin for preanesthetic sedation in cats.

OBJECTIVE: To compare the effects of oral pregabalin versus gabapentin on sedation quality and anesthesia recovery times in cats in a typical perioperative setting. ANIMALS: 50 healthy cats with > 1 kg body weight presenting for elective surgery. METHODS: In this randomized, prospective clinical trial, cats presenting to the University of California-Davis Veterinary Medical Teaching Hospital were assigned to receive buprenorphine 0.02 mg/kg IM followed by 1 of 2 oral sedation treatments: pregabalin 4 mg/kg or gabapentin 10 mg/kg. Cats were then anesthetized using a standardized protocol. Physical examination parameters and behavioral scores were measured by 2 treatment-blinded veterinarians to compare sedation levels before and after drug administration. Inadequate sedation for handling or IV catheter placement was addressed by dexmedetomidine administration. After surgery was completed, anesthesia recovery times and quality were assessed by the same veterinarians. The effects of pregabalin versus gabapentin on body temperature, respiratory rate, and heart rate were analyzed using Student t tests; behavioral assessments were analyzed using Wilcoxon signed-rank tests; and drug treatment effects on dexmedetomidine sedation rescue and frequency of delirium during anesthetic recovery were analyzed using Fisher exact tests. A P < .05 indicated statistical significance. RESULTS: There was no significant difference in change of physiologic parameters or sedation scores before and after sedation between groups. The need for rescue sedation for IV catheter placement and the incidence of emergence delirium were infrequent and similar for both treatments. CLINICAL RELEVANCE: At the doses studied, oral pregabalin and gabapentin produced indistinguishable effects as adjunctive perioperative sedation agents in cats.

Analgesic effect of the mint terpenoid L-carvone in sheep.

OBJECTIVE: To determine whether L-carvone increases the voltage threshold response to a noxious electrical stimulus in sheep. STUDY DESIGN: Prospective, blinded, randomized, crossover experimental study. ANIMALS: A group of six healthy adult sheep. METHODS: Sheep were instrumented with cranial dorsothoracic subcutaneous copper electrodes. A stimulator delivered a 10 ms square-wave stimulus at 50 pps starting at 0.1 V with a 0.2 V second-1 ramp. The stimulus stopped once two observers who were blinded to treatment noted a behavioral pain response or when a 15 V cut-off was reached. Next, 0.15 mL kg-1 of either a 50% L-carvone solution or a saline-vehicle control was administered intramuscularly, and electrical threshold responses were measured every 5-15 minutes over a 6 hour period using methods identical to the baseline. One week following the first treatment (L-carvone or control), sheep were studied using identical methods with the second treatment (control or L-carvone). Drug and time effects were evaluated using a two-way repeated measures analysis of variance, and pairwise comparisons were evaluated with Holm-Sidák tests with values of p < 0.05 considered significant. RESULTS: L-carvone significantly increased voltage threshold responses for most time points up to 75 minutes compared with baseline and with saline control. The last time point with a significantly different response between L-carvone and saline treatments was 5 hours after drug administration. The saline-vehicle control decreased voltage threshold responses at several time points after 3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Intramuscular L-carvone is analgesic in sheep, although the ethanol-propylene glycol vehicle may cause mild hyperalgesia. This study demonstrates that a food-derived compound can be used to relieve pain in a food-producing animal.

Treatment of Pain in Rabbits.

Rabbits occupy facets of veterinary medicine spanning from companion mammals, wildlife medicine, zoologic species, and research models. Therefore, analgesia is required for a variety of conditions in rabbits and is a critical component of patient care. Considerations when selecting an analgesic protocol in rabbits include timing of administration, route of administration, degree or anticipated pain, ability to access or use controlled drugs, systemic health, and any potential side effects. This review focuses on pharmacologic and locoregional management of pain in rabbits and emphasizes the need for further studies on pain management in this species.

Anesthetic Pharmacology of the Mint Extracts L-Carvone and Methyl Salicylate.

INTRODUCTION: Hydrocarbons with sufficient water solubility allosterically modulate anesthetic-sensitive ion channels. Mint extracts L-carvone and methyl salicylate water solubility exceeds modulation cutoff values for γ-amino butyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA) receptors, and type-2 voltage-gated sodium (Nav1.2) channels. We hypothesized that mint extracts modulate these channels at concentrations that anesthetize rats. METHODS: Channels were expressed separately in frog oocytes and studied using 2-electrode voltage clamp techniques at drug concentrations up to 10 mM. Normalized current effects were fit to Hill equations. Mint compounds were formulated in a lipid emulsion and administered IV to rats. When unresponsive to the tail clamp, rats were exsanguinated, and plasma drug concentrations were measured. RESULTS: Both mint compounds caused concentration-dependent inhibition of all channels except for methyl salicylate which inhibited GABAA receptors at low concentrations and potentiated at high concentrations. Plasma drug concentrations in anesthetized rats were 7.9 mM for L-carvone and 2.7 mM for methyl salicylate. This corresponded to ≥53% NMDA receptor inhibition and ≥78% Nav1.2 channel inhibition by both compounds and 30% potentiation of GABAA receptors by methyl salicylate. CONCLUSION: L-Carvone and methyl salicylate allosterically modulate cell receptor targets important to molecular actions of conventional anesthetics at concentrations that also induce general anesthesia in rats.

Pharmacokinetics and pharmacodynamics of a high concentration of buprenorphine (Simbadol) in conscious horses after subcutaneous administration.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of high-concentration formulation of buprenorphine (1.8 mg mL-1; Simbadol) following subcutaneous (SC) administration in horses. STUDY DESIGN: Prospective, randomized, crossover trial. ANIMALS: A group of six healthy adult horses weighing 521-602 kg. METHODS: On three occasions, Simbadol (0.005 mg kg-1; treatment S5), (0.0025 mg kg-1; treatment S2.5) or saline (treatment SAL) were administered SC at least 7 days apart in random order. Electrical nociceptive threshold (ENT) measured on the neck region, physiologic variables, locomotor activity, degree of restlessness and presence of excitatory signs were measured at baseline and for up to 48 hours after injection. Blood was collected for pharmacokinetic analysis at the same time intervals and plasma buprenorphine concentration (Cp) measured using liquid chromatography-tandem mass spectrometry. RESULTS: Buprenorphine was quantifiable in all horses from 15 minutes after administration up to 8-12 hours. ENT was significantly increased in treatment S2.5 compared with treatment SAL at 0.75-6 hours after treatment. Increase in locomotor activity and compulsive behavior were recorded in all horses after Simbadol, and degree of restlessness was significantly higher in treatment S5 than SAL for a sustained time. Gastrointestinal motility significantly decreased in all horses after Simbadol and returned to baseline by 16 hours after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, SC Simbadol was rapidly absorbed and Cp decreased rapidly. Side effects commonly seen in horses after opioids were observed in both Simbadol treatments, but degree of opioid-induced excitement lasted significantly longer in treatment S5. Simbadol (0.0025 mg kg-1) SC has the potential to be used clinically to treat pain in horses. However, at this dose, duration of antinociceptive effects was not longer than that reported for conventional buprenorphine, and side effects, including reduction in gastrointestinal motility and increased locomotor activity, were documented.

In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid.

BACKGROUND: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on -GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. METHODS: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, ß2 and γ2s subunits. The effects of DOMBA (0.2-10 mmol/L) and propanidid (0.001-1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received -DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. RESULTS: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5-10 and 0.5-10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. CONCLUSION: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

Comparison between the effects of postanesthetic xylazine and dexmedetomidine on characteristics of recovery from sevoflurane anesthesia in horses.

OBJECTIVE: To compare postanesthetic xylazine and dexmedetomidine on recovery characteristics from sevoflurane anesthesia in horses. STUDY DESIGN: Randomized, crossover study. ANIMALS: Six geldings, mean±standard deviation (SD) (range), 17±4 (11-24) years and 527±80 (420-660) kg. METHODS: Horses were anesthetized with sevoflurane for 60 minutes under standardized conditions for a regional limb perfusion study. In recovery, horses were administered either xylazine (200 µg kg-1) or dexmedetomidine (0.875 µg kg-1) intravenously. Recoveries were unassisted and were video-recorded for later evaluation of recovery events and quality by two individuals unaware of treatment allocation. Recovery quality was assessed using a 100 mm visual analog scale (VAS) (0=poor recovery, 100=excellent recovery), the Edinburgh Scoring System (ESS) (0-100; 100=excellent recovery) and the mean attempt interval (MAI) (longer=better). Data are mean±SD. RESULTS: All recovery quality assessments (xylazine and dexmedetomidine, respectively: VAS: 71±21 mm, 84±13 mm; ESS: 65±22, 67±30; MAI: 52±24 minutes, 60±32 minutes) and events (first limb movement: 37±8 minutes, 42±10 minutes; first attempt to lift head: 44±12 minutes, 48±9 minutes; first attempt to sternal posture: 57±28 minutes, 50±7 minutes; number of head bangs: 2.0±3.0, 0.5±0.5; time to first attempt to stand: 72±6 minutes, 78±13 minutes; time to standing: 79±14 minutes, 84±13 minutes) did not differ significantly between treatments (p>0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Recovery characteristics did not differ significantly between postanesthetic xylazine and dexmedetomidine following 1 hour of sevoflurane anesthesia in horses in this study. Further evaluations in more horses and in younger horses are required to confirm these results.

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. STUDY DESIGN: Prospective, blinded, randomized clinical study. ANIMALS: A group of 26 dogs weighing 31.7 ± 14.2 (mean ± standard deviation) kg and aged 54 ± 36 months. METHODS: All dogs were premedicated with methadone intravenously (0.2 mg kg-1) and anaesthesia induced with diazepam (0.2 mg kg-1) and propofol intravenously to effect. After induction of anaesthesia, dogs randomly received a lumbosacral epidural injection of morphine 0.1 mg kg-1 with either levobupivacaine 0.5% (1 mg kg-1; group LevoBM) or bupivacaine 0.5% (1 mg kg-1; group BM). Cardiovascular, respiratory and temperature values were recorded during the intra- and postoperative period. A visual analogue scale, subjective pain scale, sedation scale and the short form of the Glasgow pain scale were assessed every 6 hours after epidural injection during 24 hours. The ability to stand and walk, neurological deficits and other side effects were assessed at the same time points. The amount of rescue analgesia (sufentanil intraoperatively and methadone postoperatively) was recorded. RESULTS: No statistically significant differences were found between groups for any of the recorded data, with the exception of the incidence of spontaneous urination and postoperative rescue analgesia requirement. In group LevoBM four dogs spontaneously urinated at recovery while none of the dogs in group BM did (p = 0.03) and seven dogs of group LevoBM required postoperative rescue analgesia versus none of the dogs in the BM group (p = 0.005). CONCLUSIONS: and clinical relevance Epidural LevoBM is a suitable alternative to BM in healthy dogs during elective pelvic limb surgery. Epidural BM produced more urinary retention but better pain control compared to the same concentration and dose of LevoBM in dogs.

Investigation of perioperative and anesthetic variables affecting short-term survival of horses with small intestinal strangulating lesions.

OBJECTIVE: To determine if preoperative and intraoperative physiologic variables, and surgical factors correlate with survival to anesthetic recovery or hospital discharge, repeat celiotomy, and postoperative nasogastric intubation (NGT) in horses undergoing exploratory celiotomy for small intestinal (SI) strangulating lesions. STUDY DESIGN: Retrospective case series. ANIMALS: Horses that had surgical correction of SI strangulating lesions (n = 258). METHODS: Medical records (January 2000-December 2014) of horses that had surgical correction of SI strangulating lesions were reviewed. Data collection included signalment, preoperative physical examination variables, hematologic values, presence of gastric reflux, peritoneal fluid analysis, intraoperative physiologic variables, intraoperative findings/treatments, and arterial blood gas values. Risk factors for survival to anesthetic recovery and hospital discharge were determined using exact logistic regression. RESULTS: Survival to anesthetic recovery was 76% and survival to discharge after anesthetic recovery was 79%. The difference between abdominal and peripheral lactate concentrations and intraoperative tachycardia were associated with not surviving to anesthetic recovery or hospital discharge. Intraoperative hypotension, hypocapnia, and low intraoperative packed cell volume (PCV) were negative predictors of survival to anesthetic recovery. Low intraoperative PCV was also associated with NGT postoperatively. Performing resection-anastomosis and jejunocecostomy were associated with repeat celiotomy and with not surviving to hospital discharge. CONCLUSION: Several hematological and cardiorespiratory variables show good correlation with short-term survival in horses undergoing surgery for SI strangulating lesions. These variables are easily measured and could be useful for prognosticating survival in horses presenting with SI strangulating lesions.

Pharmacokinetics and pharmacodynamics of intravenous romifidine and propranolol administered alone or in combination for equine sedation.

OBJECTIVE: Propranolol has been suggested for anxiolysis in horses, but its sedation efficacy and side effects, both when administered alone and in combination with α2-adrenoceptor agonists, remain undetermined. This study aimed to document the pharmacokinetics and pharmacodynamics of propranolol, romifidine and their combination. STUDY DESIGN: Randomized, crossover study. ANIMALS: Six adult horses weighing 561 ± 48 kg. METHODS: Propranolol (1 mg kg-1; treatment P), romifidine (0.1 mg kg-1; treatment R) or their combination (treatment PR) were administered intravenously with a minimum of 1 week between treatments. Alertness, behavioral responsiveness (visual and tactile) and physiologic variables were measured before and up to 960 minutes after drug administration. Blood was collected for blood gas and acid-base analyses and measurement of plasma drug concentrations. Data were analyzed using repeated-measures analysis of variance or Friedman with Holm-Sidak and Wilcoxon rank-sum tests (p < 0.05). RESULTS: Systemic clearance significantly decreased and the area under the concentration-time curve significantly increased for both drugs in PR compared with P and R. Both PR and R decreased behavioral responsiveness and resulted in sedation for up to 240 and 480 minutes, respectively. Sedation was deeper in PR for the first 16 minutes. Heart rate significantly decreased in all treatments for at least 60 minutes, and PR significantly increased the incidence of severe bradycardia (<20 beats minute-1). CONCLUSIONS AND CLINICAL RELEVANCE: Although not associated with reduced behavioral responsiveness or sedation alone, propranolol augmented romifidine sedation, probably through alterations in romifidine pharmacokinetics, in horses administered PR. The occurrence of severe bradycardia warrants caution in the co-administration of these drugs at the doses studied.

Clinical comparison of two regimens of lidocaine infusion in horses undergoing laparotomy for colic.

OBJECTIVE: To compare, in horses undergoing laparotomy for colic, the effects of administering or not administering a loading intravenous (IV) bolus of lidocaine prior to its constant rate infusion (CRI). Effects investigated during isoflurane anaesthesia were end-tidal isoflurane concentration (Fe'ISO), cardiovascular function, anaesthetic stability and the quality of recovery. STUDY DESIGN: Prospective, randomized clinical study. ANIMALS: Thirty-six client-owned horses. METHODS: Horses were assigned randomly to receive lidocaine as a CRI (50 µg kg(-1)  minute(-1) ) either preceded (LB) or not preceded (L) by a loading dose (1.5 mg kg(-1) IV over 15 minutes). Lidocaine infusion (LInf) was started (T0) within 20 minutes after induction of general anaesthesia and discontinued approximately 30 minutes before the end of surgery. Anaesthetic depth, Fe'ISO, intra-operative physiological parameters and quality of recovery were assessed or measured. Data were analysed using one-way anova, t-test, Fisher test, Wilcoxon and Kruskal-Wallis tests as appropriate (p < 0.05). RESULTS: Mean ± SD Fe'ISO was 1.21 ± 0.08% in group LB and 1.23 ± 0.06% in group L. Heart rate was significantly higher in group L than in group LB at times T5-T15, T25, T35 and T95. No difference was found between groups in other measured physiological values, nor in any measure taken to improve these parameters. Recovery phase was comparable and satisfactory in all but one full term pregnant horse in group L which fractured a femur during recovery. CONCLUSION: Preloading with a lidocaine bolus prior to a CRI of lidocaine did not influence isoflurane requirements, cardiopulmonary effects (other than a reduction in heart rate at some time points) or recovery compared to no preloading bolus. CLINICAL RELEVANCE: A loading dose of lidocaine prior to CRI does not confer any advantage in horses undergoing laparotomy for colic.