Long-acting injectable methadone (methadone-fluconazole) provides safe and effective postoperative analgesia in a randomized clinical trial for dogs undergoing soft tissue surgery.

OBJECTIVE: To assess the pharmacokinetics, clinical efficacy, and adverse effects of injectable methadone with the pharmacokinetic enhancer fluconazole (methadone-fluconazole), compared with the standard formulation of injectable methadone, in dogs after ovariohysterectomy. We hypothesized that 2 doses of methadone-fluconazole would provide 24 hours of postoperative analgesia. ANIMALS: 3 purpose-bred dogs (pharmacokinetic preliminary study) and 42 female dogs from local shelters (clinical trial) were included. PROCEDURES: Pharmacokinetics were preliminarily determined. Clinical trial client-owned dogs were blocked by body weight into treatment groups: standard methadone group (methadone standard formulation, 0.5 mg/kg, SC, q 4 h; n = 20) or methadone-fluconazole group (0.5 mg/kg methadone with 2.5 mg/kg fluconazole, SC, repeated once at 6 h; n = 22). All dogs also received acepromazine, propofol, and isoflurane. Surgeries were performed by experienced surgeons, and dogs were monitored perioperatively using the Glasgow Composite Measure Pain Scale-Short Form (CMPS-SF) and sedation scales. Evaluators were masked to treatment. RESULTS: Findings from pharmacokinetic preliminary studies supported that 2 doses of methadone-fluconazole provide 24 hours of drug exposure. The clinical trial had no significant differences in treatment failures or postoperative CMPS-SF scores between treatments. One dog (methadone-fluconazole group) had CMPS-SF > 6 and received rescue analgesia. All dogs had moderate sedation or less by 1 hour (methadone-fluconazole group) or 4 hours (standard methadone group) postoperatively. Sedation was completely resolved in all dogs the day after surgery. CLINICAL RELEVANCE: Methadone-fluconazole with twice-daily administration was well tolerated and provided effective postoperative analgesia for dogs undergoing ovariohysterectomy. Clinical compliance and postoperative pain control may improve with an effective twice-daily formulation.

Perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy.

OBJECTIVE: To determine perioperative analgesia associated with oral administration of a novel methadone-fluconazole-naltrexone formulation in dogs undergoing routine ovariohysterectomy. ANIMALS: 43 healthy female dogs. PROCEDURES: Dogs were randomly assigned to receive the methadone-fluconazole-naltrexone formulation at 1 of 2 dosages (0.5 mg/kg, 2.5 mg/kg, and 0.125 mg/kg, respectively, or 1.0 mg/kg, 5.0 mg/kg, and 0.25 mg/kg, respectively, PO, q 12 h, starting the evening before surgery; n = 15 each) or methadone alone (0.5 mg/kg, SC, q 4 h starting the morning of surgery; 13). Dogs were sedated with acepromazine, and anesthesia was induced with propofol and maintained with isoflurane. A standard ovariohysterectomy was performed by experienced surgeons. Sedation and pain severity (determined with the Glasgow Composite Pain Scale-short form [GCPS-SF]) were scored for 48 hours after surgery. Rescue analgesia was to be provided if the GCPS-SF score was > 6. Dogs also received carprofen starting the day after surgery. RESULTS: None of the dogs required rescue analgesia. The highest recorded GCPS-SF score was 4. A significant difference in GCPS-SF score among groups was identified at 6:30 am the day after surgery, but not at any other time. The most common adverse effect was perioperative vomiting, which occurred in 11 of the 43 dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of a methadone-fluconazole-naltrexone formulation at either of 2 dosages every 12 hours (3 total doses) was as effective as SC administration of methadone alone every 4 hours (4 total doses) in dogs undergoing routine ovariohysterectomy. Incorporation of naltrexone in the novel formulation may provide a deterrent to human opioid abuse or misuse.

Clinical and pharmacokinetic interactions between oral fluconazole and intravenous ketamine and midazolam in dogs.

OBJECTIVE: To evaluate drug interactions between fluconazole and the intravenous (IV) anesthetic induction agents, ketamine and midazolam. STUDY DESIGN: Randomized parallel study. ANIMALS: A group of 12 adult healthy Beagle dogs. METHODS: Dogs were randomly allocated to two groups of six dogs. Dogs in group KM were administered IV ketamine (7 mg kg-1) and IV midazolam (0.25 mg kg-1), and dogs in group KMF were administered fluconazole (5 mg kg-1) orally 12 and 24 hours prior to ketamine-midazolam using the same doses as KM. Sedation scores (0-4) were assigned by investigators unaware of group assignment. Heart rate (HR) and times to sternal and standing were obtained and compared between groups for differences with p < 0.05 considered statistically significant. Blood was obtained and plasma drug concentrations were measured using liquid chromatography-mass spectrometry. RESULTS: The times to sternal, mean 32.3 and 24.6 minutes, for groups KMF and KM, respectively, were not different between the groups. The time to standing, 73 and 36 minutes in groups KMF and KM, respectively, was significantly different (p = 0.002). The duration of elevated HR compared with baseline was longer in KMF (110 minutes) than in KM (25 minutes) (p < 0.05). In group KMF, one dog developed hyperthermia (40.6 °C), which resolved spontaneously. The clearance of ketamine and midazolam was significantly slower (approximately 50%) and the area under the curves were significantly higher (two-fold) in group KMF (p = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: A significant interaction between oral fluconazole and IV ketamine-midazolam occurred, but the effects appear minor in healthy dogs. Based on these data, a single dose of ketamine-midazolam is not contraindicated in dogs treated with fluconazole, but the duration of effects and pharmacokinetics are altered.