Pharmacokinetics of Extended-release Buprenorphine and Clinical Efficacy for Postoperative Pain Management in the Domestic Ferret (Mustela putorius furo)

Abstract

Buprenorphine hydrochloride (Bup-HCl) is a common injectable opioid analgesic. In ferrets, Bup-HCl must be administered every 8 to 12 h to maintain clinical efficacy. Extended-release analgesics offer multiple advantages, including reduced handling and injection frequency, improved compliance, and increased protection from end-of-dose failure. Although efficacy of extended-release buprenorphine formulations has been demonstrated in other species, their use in the domestic ferret has not been investigated. In this study, we evaluated the pharmacokinetics of a compounded polymeric formulation of buprenorphine (Bup-ER) and a pharmaceutical-grade, FDA-indexed liposomal suspension (Bup-XR). Two doses each of Bup-ER (0.12 and 0.2 mg/kg) and Bup-XR (0.2 and 0.6 mg/kg SC) were administered to young adult female ferrets and plasma concentrations were measured between 0 and 96 h (n = 4 animals per timepoint). All doses of both drugs achieved therapeutic plasma levels by 30 min. Furthermore, high-dose Bup-XR maintained therapeutic levels for 72 h, followed by high-dose Bup-ER (less than 48 h), low-dose Bup-XR (24 h), and low-dose Bup-ER (less than 24 h). In this study, we also developed a pain scoring system and utilized this to compare analgesic efficacy between single high-dose Bup-XR (0.6 mg/kg SC) and a standard postoperative course of Bup-HCl (0.02 mg/kg SC every 10 to 12 h for 8 doses) after ovariohysterectomy. Ferrets receiving Bup-XR had significantly lower respiratory rate and posture scores in the first 24 h postoperatively than did those that received Bup-HCl and were less likely to react to palpation of the surgical incision. Of note, ferrets that received high-dose Bup-ER had a significantly higher incidence of injection site reactions than ferrets that received Bup-HCl (P = 0.0137). This study demonstrates that a single dose of Bup-XR (0.6 mg/kg SC) is a safe and effective analgesic in female ferrets, with a duration of action up to 72 h and minimal side effects, offering a refinement to analgesia in this species.

Figure 1.

Study timeline. (A) Each cohort of 12 ferrets underwent 2 PK studies and one efficacy study, with all study phases separated by a washout period of at least 2 wk. For the PK studies, ferrets in cohort 1 received low-dose Bup-XR (0.2 mg/kg SC) and high-dose Bup-XR (0.6 mg/kg SC), and ferrets in cohort 2 received low-dose Bup-ER (0.12 mg/kg SC) and high-dose Bup-ER (0.2 mg/kg SC). For the clinical efficacy study, each cohort underwent ovariohysterectomy, followed by administration of an opioid regimen and clinical scoring. All ferrets in cohort 1 (n = 12) received Bup-HCl (0.02 mg/kg SC every 10 to 12 h for 8 doses) for postoperative analgesia. Ferrets in cohort 2 received either a single injection of high-dose Bup-XR (0.6 mg/kg SC; n = 9) or high-dose Bup-ER (0.2 mg/kg SC; n = 2). One ferret originally assigned to the Bup-XR group received an incomplete dose and was thus withdrawn from the study prior to clinical scoring. (B) Injection site reactions (ISRs) observed in ferrets in cohort 2. ‘Y’ indicates the presence of ISR; ‘N’ indicates the absence of ISR; and ‘W’ indicates one ferret that received an incomplete dose of Bup-XR, and was thus withdrawn from the efficacy study.

Figure 2.

Postoperative pain scoring system for ferrets. After administration of postoperative analgesia, the cumulative score is expected to be less than or equal to 3 on the evening of surgery, less than or equal to 2 on postoperative days 1 to 2, and less than 2 thereafter. Consider rescue analgesia if an animal’s cumulative score is 3 or higher starting on postoperative day 1, or if an animal receives a score of 2 in any single category in section 1 or section 2. Changes in the general attitude, rectal temperature, and reaction to incisional palpation are not absolute indications for rescue analgesia, but should be considered in the context of the complete clinical picture.

Figure 3.

Time compared with buprenorphine plasma concentration (ng/mL) of 2 sustained-release formulations. The therapeutic level (0.5 ng/mL) is indicated by the dotted line. The dashed line indicates the one-phase decay function fitted to each data set. (A) Low-dose Bup-XR achieved therapeutic plasma concentrations (TPC) by 15 min postadministration and remained above the therapeutic level for 24 h. (B) High-dose Bup-XR achieved TPC by 30 min postadministration (the first timepoint assessed) and remained at or above the therapeutic level for 72 h. (C) Low-dose Bup-ER achieved TPC by 15 min postadministration but mean drug concentration dropped below the therapeutic level by 24 h. (D) High-dose Bup-ER achieved TPC by 15 min postadministration and dropped below therapeutic levels by 48 h.

Figure 4.

Comparison of pain scores between ferrets receiving subcutaneous Bup-HCl (0.02 mg/kg) or a single dose of Bup-XR (0.6 mg/kg) for management of postoperative pain. Scores from all observers were averaged at each timepoint, and data were analyzed by repeated measures ANOVA (A–C) or a mixed effects model (D). (A) Ferrets receiving Bup-XR had significantly lower average resting respiratory rate scores compared with ferrets receiving Bup-HCl (P < 0.0001), with no significant effect of individual subject (P = 0.2556). Resting respiratory rate score also decreased significantly over time in both groups (P < 0.0001). (B) Average orbital tightening score decreased significantly over time in all ferrets (P < 0.0001). There was no effect of opioid choice (P = 0.3585) or of individual subject (P = 0.0933) on orbital tightening score. (C) Ferrets receiving Bup-XR had significantly lower average posture score compared with ferrets receiving Bup-HCl (P < 0.0001), with no significant effect of individual subject (P = 0.5143). Posture score also decreased significantly over time in both groups (P < 0.0001). (D) There was no effect of opioid choice on rectal temperature (°F) (P = 0.3794) or rectal temperature score (P = 0.1804). Rectal temperature significantly decreased over time in all ferrets (P < 0.0001). POD, postoperative day.

Figure 5.

Comparison of incisional scores between ferrets receiving subcutaneous Bup-HCl (0.02 mg/kg) or a single dose of Bup-XR (0.6 mg/kg) for management of postoperative pain. Scores from all observers were averaged at each timepoint, and data were analyzed by repeated measures ANOVA. (A) Incisional erythema score was not significantly different between opioid groups (P = 0.2646) but varied significantly between individual ferrets (P = 0.0011) and with time (P < 0.0001). (B) Incisional swelling score was not significantly different between opioid groups (P = 0.2943) but varied significantly between individual ferrets (P < 0.0001) and with time (P < 0.0001). (C) There was a significant overall effect of opioid on reaction to incisional palpation (P = 0.0021) on repeated measures ANOVA, but no significant difference between individual timepoints on multiple comparisons testing.

Figure 6.

Representative images of injection site reaction (ISR) following SC injection of high-dose Bup-ER. Hematoxylin and eosin staining of a fine needle aspirate sample revealed a mixed inflammatory cell population without bacteria or degenerative changes, consistent with a sterile abscess.