Analgesic Efficacy of a Long-Acting Transdermal Buprenorphine in Rats (Rattus norvegicus)
Zorbium is the first long-acting transdermal buprenorphine (LAT-bup) approved by the FDA for relieving postoperative pain in cats for 72 h. This study aimed to investigate LAT-bup’s efficacy for attenuating postoperative mechanical and thermal hypersensitivity in a rat incisional pain model. We hypothesized that a high dose of LAT-bup would attenuate mechanical and thermal hypersensitivities more effectively than a low dose in rats for 96 h postoperatively. Two experiments were conducted. In experiment 1, a total of 34 Sprague–Dawley rats were randomly assigned into one of 4 treatment groups: (1) saline (0.9% NaCl, 5 mL/kg, transdermal); (2) buprenorphine extended-release (Bup-ER; 1.2 mg/kg, SC); (3) low-dose long-acting transdermal buprenorphine (LAT-bup low; 5 mg/kg, transdermal); or (4) high-dose long-acting transdermal buprenorphine (LAT-bup high; 10 mg/kg, transdermal). One hour after drug application, a 1-cm incision was made on the left plantar paw of the rat under isoflurane anesthesia. Mechanical and thermal hypersensitivity were measured at −24 h (24 h before surgery) and at 4, 24, 48, 72, and 96 h postsurgery. In experiment 2, 49 rats were used to measure plasma buprenorphine levels at various time points: 20 and 40 min and 1, 4, 24, 48, 72, and 96 h. Clinical observations were recorded daily, and a gross necropsy was performed at 96 h. Bup-ER and high-dose LAT-bup effectively reduced mechanical hypersensitivity from 4 to 48 h. However, neither the low nor high doses of LAT-bup attenuated thermal hypersensitivity. Plasma buprenorphine concentrations remained above 1 ng/mL from 4 to 96 h across all groups. This study demonstrates that high-dose LAT-bup attenuated postoperative mechanical hypersensitivity as effectively as Bup-ER for up to 48 h in this rat incisional pain model. Based on these findings, we recommend LAT-bup at 10 mg/kg for minor incisional pain procedures in rats.
Body weight. Body weight (mean ± SEM) recorded daily for the saline, Bup-ER, LAT-bup low (5 mg/kg), and LAT-bup high (10 mg/kg) groups. The arrow denotes the time of surgery at the 0-h mark.
Mechanical hypersensitivity of the ipsilateral (surgical) hind paw. Mechanical hypersensitivity was evaluated by counting the number of paw withdrawals (in incidents; mean ± SEM) of the ipsilateral hind paw in response to a mechanical stimulus. The x-axis represents time, and the y-axis shows the number of paw withdrawals. A lower number of paw withdrawal counts suggests reduced hypersensitivity. The arrow denotes the time of surgery at the 0-h mark. *, P < 0.05, significant difference from the baseline (−24 h) value within the same treatment group. #, P < 0.05, significant difference when compared with the saline group.
Mechanical hypersensitivity of the contralateral (nonsurgical) hind paw. Mechanical hypersensitivity was evaluated by counting the number of paw withdrawals (in incidents; mean ± SEM) of the contralateral hind paw in response to a mechanical stimulus. The x-axis represents time, and the y-axis shows the number of paw withdrawals. A lower number of paw withdrawal counts suggests reduced hypersensitivity. The arrow denotes the time of surgery at the 0-h mark.
Thermal hypersensitivity of the ipsilateral (surgical) hind paw. Thermal hypersensitivity was evaluated by calculating the thermal latency (in seconds; mean ± SEM) of the ipsilateral hind paw to a thermal stimulus. The x-axis represents time, and the y-axis shows the thermal latency. A shorter thermal latency suggests higher hypersensitivity. The arrow denotes the time of surgery at the 0-h mark. *, P < 0.05, significant difference from the baseline (−24 h) value within the same treatment group. #, P < 0.05, significant difference when compared with the saline group.
Thermal hypersensitivity of the contralateral (nonsurgical) hind paw. Thermal hypersensitivity was evaluated by calculating the thermal latency (in seconds; mean ± SEM) of the contralateral hind paw to a thermal stimulus. The x-axis represents time, and the y-axis shows the thermal latency. A shorter thermal latency suggests higher hypersensitivity. The arrow denotes the time of surgery at the 0-h mark.
Gross necropsy. Bup-ER group example injection site reaction.
Buprenorphine plasma concentration. Plasma concentration (ng/mL; mean ± SEM) in rats treated with LAT-bup low (5 mg/kg) or LAT-bup high (10 mg/kg) was measured at each time point (n = 3/group/time point; n = 2 for LAT-bup high 96 h). Sampling occurred at 20 and 40 min and 1, 4, 24, 48, 72, and 96 h postadministration.
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