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

Abstract

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.

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

“…Standard ovariohysterectomies were performed by experienced faculty surgeons (EEK, DAU, KAB, AJC, BC) between 8:00 am and 12:10 pm, with anesthesia monitored by registered veterinary nurses (GJ, RJO) and supervised by an experienced boardcertified anesthesiologist (DEM) according to previously published methods. 11 Following premedication, IV catheter placement started at 7:30 am (± 30 minutes). Anesthesia was induced with propofol (IVAOES Animal Health; 4 mg/kg, IV) titrated until intubation was possible.…”

“…A CMPS-SF total score > 6 (or > 5 if the dog was nonmobile) was used as the cutoff for treatment failure and for which rescue analgesia (morphine, 0.25 mg/kg, SC) was administered. 11 Treatment failure was the pivotal efficacy outcome. The secondary outcome was CMPS-SF total score.…”

“…The a priori sample size was estimated based on the expected proportion of treatment success at least 0.95 for the positive control (standard methadone) as previously reported in dogs undergoing ovariohysterectomies. 11 The expected proportion of efficacy for methadonefluconazole was set to 0.6 (the previously reported success rate of a placebo in dogs undergoing soft tissue surgery). 12,13 The desired power of 0.8 and an alpha of 0.05 yielded a sample size of at least 18 animals per treatment.…”

“…The sample size analysis for the secondary variable, CMPS-SF total score, was based on an expected mean of 2 for standard methadone and 3 for methadone-fluconazole, based on a drug proven effective in soft tissue surgery in dogs, with standard deviations of 1, an alpha = 0.05 and power of 0.8 yielded a sample size of 12 animals per group. [11][12][13] Based on these sample size calculations, at least 20 animals per treatment were enrolled. For the clinical trial data, the proportion of treatment failures was compared using the Fisher's exact test with P < 0.05 considered significant.…”

“…orally administered methadone in dogs by inhibiting this rapid metabolism and resulting in prolonged central opioid effects and clinical analgesia. 7,[9][10][11] The pharmacokinetic result of this interaction is increased methadone oral bioavailability (when both drugs are administered orally) and a prolonged halflife of methadone presumably through decreased clearance. To the authors' knowledge, the effect of fluconazole on parenteral methadone metabolism has not been reported.…”