Dosing protocols to improve the efficacy of butorphanol in healthy dogs

Abstract

Opioid analgesics are important for perioperative pain management protocols due to their high analgesic efficacy; however, some opioids, such as butorphanol, have been reported to have a short duration of central opioid effect. The objective of this study was to compare the pharmacokinetics and effects of butorphanol in dogs after various routes of administration and to investigate strategies to prolong the duration of activity of butorphanol. Twelve Beagles (6 male, 6 female) were enrolled. Six dogs were randomly allocated to each butorphanol treatment protocol: IV (0.4 mg/kg), IV loading dose (0.2 mg/kg) with IV constant rate infusion (CRI) (0.2 mg/kg/hr for 8 hours), subcutaneous (SC) (0.4 mg/kg), SC (0.8 mg/kg) with an equal volume sodium bicarbonate (SC-bicarbonate) and IV after administration of cytochrome P450 (CYP) inhibitors. We hypothesized that; (1) administration of butorphanol as a CRI would produce a longer duration of central opioid effects and more consistent plasma concentrations than an IV bolus administration, (2) SC administration of butorphanol-bicarbonate suspension would produce a longer duration of opioid effects and more detectable plasma concentrations than SC administration of butorphanol alone, and (3) administration of CYP inhibitors prior to IV bolus administration would prolong duration of opioid effects and butorphanol plasma concentrations compared to IV bolus alone. Hypothermia, an opioid effect paralleling antinociception in dogs, and sedation were measured. Pharmacokinetics and purported CYP inhibitor effects on butorphanol pharmacokinetics were determined. Rectal temperatures were significantly lower than baseline from 1.5-4 hr (IV), 1-5 hr (CRI) and 2-7 hr (SC-bicarbonate), but not after SC. All treatments resulted in sedation. The elimination half-life of butorphanol was approximately 1.5 hr. Butorphanol via the SC-bicarbonate route had a lower bioavailability (61%) relative to SC with no sustained release observed. The mean steady state plasma concentration for CRI was 43.1 ng/mL. Purported CYP inhibitors had minor effects on butorphanol pharmacokinetics. Further studies are required to determine antinociception and clinical analgesia of these protocols.