The construction and application of a population physiologically based pharmacokinetic model for methadone in Beagles and Greyhounds

Methadone is an opioid analgesic in veterinary and human medicine. To help develop appropriate pain management practices and to develop a quantitative model for predicting methadone dosimetry, a flow‐limited multiroute physiologically based pharmacokinetic (PBPK) model for methadone in dogs constructed with Berkeley Madonna? was developed. The model accounts for intravenous (IV), subcutaneous (SC), and oral administrations, and compartmentalizes the body into different components. This model was calibrated from plasma pharmacokinetic data after IV administration of methadone in Beagles and Greyhounds. The calibrated model was evaluated with independent data in both breeds of dogs. One advantage of this model is that most physiological parameter values for Greyhounds were taken directly from the original literature. The developed model simulates available pharmacokinetic data for plasma concentrations well for both breeds. After conducting regression analysis, all simulated datasets produced an R ² > 0.80 when compared to the measured plasma concentrations. Comparative analysis of the dosimetry of methadone between the breeds suggested that Greyhounds had ~50% lower 24‐hr area under the curve (AUC) of plasma or brain concentrations than in Beagles. Furthermore, population analysis was conducted with this study. This model can be used to predict methadone concentrations in multiple dog breeds using breed‐specific parameters.     

Effects of perioperative saphenous and sciatic nerve blocks,lumbosacral epidural or morphine–lidocaine–ketamine infusion on postoperative pain and sedation in dogs undergoing tibial plateau leveling osteotomy

ObjectiveTo compare the quality of postoperative analgesia and sedation after preoperative saphenous and sciatic nerve blockade, preoperative lumbosacral epidural injection and perioperative intravenous (IV) morphine, lidocaine and ketamine infusions in dogs undergoing stifle arthroscopy and tibial plateau leveling osteotomy (TPLO) under general anesthesia.Study designProspective, blinded, randomized, clinical comparison study.AnimalsA total of 45 dogs weighing 33.9 (15.9–56.7) kg and aged 5.2 (1.0–12.0) years, mean (range), undergoing elective unilateral TPLO for spontaneous cranial cruciate ligament rupture.MethodsClient-owned dogs were enrolled. Dogs were randomly assigned to one of three groups: group MLK, perioperative IV morphine, lidocaine and ketamine infusion; group EPID, lumbosacral epidural with ropivacaine and morphine; or group SSNB, saphenous and sciatic nerve blockade with ropivacaine. Routine stifle arthroscopy followed by TPLO surgery was performed. Sedation and pain scores were assessed at 0, 2, 4, 8 and 24 hours following extubation. Rescue analgesia was administered as prescribed by Glasgow composite pain score–short form score >5.ResultsSedation scores for MLK were higher than EPID and SSNB. Pain scores for SSNB were lower than those for EPID and MLK. No significant differences were found in anesthesia duration or surgery duration among groups. No dogs required rescue analgesia.Conclusions and clinical relevanceAlthough analgesia was adequate in all groups, the best combination of analgesia without increased sedation was recorded for SSNB.     

Immobilization of African buffaloes (Syncerus caffer) using etorphine–midazolam compared with etorphine–azaperone

ObjectiveTo compare induction times and physiological effects of etorphine–azaperone with etorphine–midazolam immobilization in African buffaloes.Study designRandomized crossover study.AnimalsA group of 10 adult buffalo bulls (mean body weight 353 kg).MethodsEtorphine–azaperone (treatment EA; 0.015 and 0.15 mg kg^–1, respectively) and etorphine–midazolam (treatment EM; 0.015 and 0.15 mg kg^–1, respectively) were administered once to buffaloes, 1 week apart. Once in sternal recumbency, buffaloes were instrumented and physiological variables recorded at 5 minute intervals, from 5 minutes to 20 minutes. Naltrexone (20 mg mg^–1 etorphine dose) was administered intravenously at 40 minutes. Induction (dart placement to recumbency) and recovery (naltrexone administration to standing) times were recorded. Arterial blood samples were analysed at 5 and 20 minutes. Physiological data were compared between treatments using a general linear mixed model and reported as mean ± standard deviation. Time data were compared using Mann-Whitney U test and reported as median (interquartile range) with p ≤ 0.05.ResultsActual drug doses administered for etorphine, azaperone and midazolam were 0.015 ± 0.001, 0.15 ± 0.01 and 0.16 ± 0.02 mg kg^–1, respectively. Induction time for treatment EA was 3.3 (3.6) minutes and not different from 3.2 (3.2) minutes for treatment EM. The overall mean arterial blood pressure was significantly lower for treatment EA (102 ± 25 mmHg) than that for treatment EM (163 ± 18 mmHg) (p < 0.001). The PaO₂ for treatment EA (37 ± 12 mmHg; 5.0 ± 1.6 kPa) was not different from that for treatment EM (43 ± 8 mmHg; 5.8 ± 1.1 kPa). Recovery time was 0.8 (0.6) minutes for treatment EA and did not differ from 1.1 (0.6) minutes for treatment EM.Conclusions and clinical relevanceTreatment EA was as effective as treatment EM for immobilization in this study. However, systemic arterial hypertension was a concern with treatment EM, and both combinations produced clinically relevant hypoxaemia. Supplemental oxygen administration is recommended with both drug combinations.     

Pain management in horses and farm animals

Objective: This review discusses the different analgesic drugs and routes of administration used in large animals for acute pain management. General guidelines and doses are given to assist in choosing techniques that provide effective analgesia. Etiology: Noxious stimuli are perceived, recognized, and localized by specialized sensory systems located at spinal and supraspinal levels. Diagnosis: Localizing the source of the noxious stimulus as well as understanding the behavioral aspects and physiological changes that result from such insult is important to adequately diagnose and treat pain. Pain assessment is far from being definite and objective; not only are there species differences, but also individual variation. In addition, the behavioral and physiological manifestations vary with the acute or chronic nature of pain. Therapy: Pain management should include (1) selecting drugs that better control the type of pain elicited by the insult; (2) selecting techniques of analgesic drug administration that act on pathways or anatomical locations where the nociceptive information is being processed or originating from; (3) combining analgesic drugs that act on different pain pathways; and (4) provide the best possible comfort for the animal. Prognosis: Providing pain relief improves the animal's well being and outcome; however, interpreting and diagnosing pain remains difficult. Continuing research in pain management will contribute to the evaluation of the pathophysiology of pain, pain assessment, and newer analgesic drugs and techniques.     

Determination of the effective dosage of tiletamine–zolazepam–ketamine–xylazine,with or without methadone,in dogs

ObjectiveTo determine the effective dosage of the combination tiletamine–zolazepam–ketamine–xylazine (TKX), with or without methadone, in dogs.Study designProspective, randomized, experimental study.AnimalsA total of 29 dogs.MethodsDogs were randomly administered TKX (group TKX, n = 13) or combined with 0.3 mg kg^–1 of methadone (group TKXM, n = 16) intramuscularly. The TKX solution contained tiletamine (50 mg mL^–1), zolazepam (50 mg mL^–1), ketamine (80 mg mL^–1) and xylazine (20 mg mL^–1). The effective dosages for immobility in 50% and 95% of the population (ED₅₀ and ED₉₅) were estimated using the up-and-down method. Approximately 20 minutes after drug administration, a skin incision was performed and the response was judged as positive or negative if the dogs moved or did not move, respectively. The TKX volume for the subsequent dog in the same group was increased or decreased by 0.005 mL kg^–1 if the response of the previous dog was positive or negative, respectively. Heart and respiratory rates, and sedation/anesthesia scores (range 0–21) were recorded before and 15 minutes after drug administration.ResultsEstimated ED₅₀ and ED₉₅ (95% confidence intervals) were: TKX, 0.025 (0.020–0.029) and 0.026 (0.010–0.042) mL kg^–1; TKXM, 0.022 (0.018–0.025) and 0.033 (0.017–0.049) mL kg^–1. Median (interquartile range) scores for sedation/anesthesia were 17 (16–18) and 17 (15–20), and times until lateral recumbency were 5 (4–6) and 6 (4–10) minutes in TKX and TKXM, respectively (p > 0.05). In both groups heart and respiratory rates decreased, but values remained acceptable for anesthetized dogs.Conclusions and clinical relevanceThe results provide a guide for volumes of TKX and TKXM in dogs requiring restraint for minimally invasive procedures. Inclusion of methadone in the TKX combination did not influence ED₅₀.     

Evaluation of analgesic and physiologic effects of epidural morphine administered at a thoracic or lumbar level in dogs undergoing thoracotomy

ObjectiveTo evaluate the analgesic and physiological effects of epidural morphine administered at the sixth and seventh lumbar or the fifth and sixth thoracic vertebrae in dogs undergoing thoracotomy.Study designProspective, randomized, blinded trial.AnimalsFourteen mixed-breed dogs, weighing 8.6 ± 1.4 kg.MethodsThe animals received acepromazine (0.1 mg kg^?1) IM and anesthesia was induced with propofol (4 mg kg^?1) IV. The lumbosacral space was punctured and an epidural catheter was inserted up to the region between the sixth and seventh lumbar vertebrae (L, n = 6) or up to the fifth or sixth intercostal space (T, n = 8). The dogs were allowed to recover and after radiographic confirmation of correct catheter position, anesthesia was reinduced with propofol IV and maintained with 1.7% isoflurane. Following stabilization of monitored parameters, animals received morphine (0.1 mg kg^?1) diluted in 0.9% NaCl to a final volume of 0.25 mL kg^?1 via the epidural catheter, and after 40 minutes, thoracotomy was initiated. Heart rate and rhythm, systolic, mean and diastolic arterial pressures, respiratory rate, arterial hemoglobin oxygen saturation, partial pressure of expired CO₂ and body temperature were measured immediately before the epidural administration of morphine (0 minute) and every 10 minutes during the anesthetic period. The Melbourne pain scale and the visual analog scale were used to assess post-operative pain. The evaluation began 3 hours after the epidural administration of morphine and occurred each hour until rescue analgesia.ResultsThere were no important variations in the physiological parameters during the anesthetic period. The post-operative analgesic period differed between the groups, being longer in T (9.9 ± 1.6 hours) compared with L (5.8 ± 0.8 hours).ConclusionsThe use of morphine, at a volume of 0.25 mL kg^?1, administered epidurally over the thoracic vertebrae provided longer lasting analgesia than when deposited over the lumbar vertebrae.Clinical relevanceThe deposition of epidural morphine provided longer lasting analgesia when administered near to the innervation of the injured tissue without increasing side effects.     

Intravenous and sublingual buprenorphine in horses: pharmacokinetics and influence of sampling site

ObjectiveTo describe the pharmacokinetics and adverse effects of intravenous (IV) and sublingual (SL) buprenorphine in horses, and to determine the effect of sampling site on plasma concentrations after SL administration.Study designRandomized crossover experiment; prospective study.AnimalsEleven healthy adult horses between 6 and 20 years of age and weighing 487–592 kg.MethodsIn the first phase; buprenorphine was administered as a single IV or SL dose (0.006 mg kg^?1) and pharmacokinetic parameters were determined for each route of administration using a noncompartmental model. In the second phase; the jugular and lateral thoracic veins were catheterized for simultaneous venous blood sampling, following a dose of 0.006 mg kg^?1 SL buprenorphine. For both phases, plasma buprenorphine concentrations were measured using ultra-performance liquid chromatography with mass spectrometry. At each sampling period, horses were assessed for behavioral excitement and gastrointestinal motility.ResultsFollowing IV administration, buprenorphine mean ± SD half-life was 5.79 ± 1.09 hours. Systemic clearance (Cl) following IV administration was 6.13 ± 0.86 mL kg^?1 minute^?1 and volume of distribution at steady-state was 3.16 ± 0.65 L kg^?1. Following IV administration, horses showed signs of excitement. Gastrointestinal sounds were decreased following both routes of administration; however, none of the horses exhibited signs of colic. There was a significant discrepancy between plasma buprenorphine concentrations measured in the jugular vein versus the lateral thoracic vein following phase 2, thus pharmacokinetic parameters following SL buprenorphine are not reported.Conclusions and clinical relevanceBuprenorphine has a long plasma half-life and results in plasma concentrations that are consistent with analgesia in other species for up to 4 hours following IV administration of this dose in horses. While buprenorphine is absorbed into the circulation following SL administration, jugular venous sampling gave a false measurement of the quantity absorbed and should not be used to study the uptake from SL administration.