Extended-release Buprenorphine, an FDAindexed Analgesic, Attenuates Mechanical Hypersensitivity in Rats (Rattus norvegicus)

Abstract

A new extended-release buprenorphine (XR), an FDA-indexed analgesic, has recently become available to the laboratoryanimal community. However, the effectiveness and dosing of XR has not been extensively evaluated for rats. We investigatedXR’s effectiveness in attenuating postoperative hypersensitivity in a rat incisional pain model. We hypothesized that highdose of XR would attenuate mechanical and thermal hypersensitivity more effectively than the low dose of XR in this model. We performed 2 experiments. In experiment 1, male adult Sprague–Dawley rats (n = 31) were randomly assigned to 1 of the 4 treatment groups: 1) saline (saline, 0.9% NaCl, 5 mL/kg, SC, once); 2) sustained-release buprenorphine (Bup-SR; 1.2 mg/kg, SC, once), 3) low-dose extended-release buprenorphine (XR-Lo; 0.65 mg/kg, SC, once), and 4) high-dose extended-releasebuprenorphine (XR-Hi; 1.3 mg/kg, SC, once). After drug administration, a 1 cm skin incision was made on the plantar hind paw under anesthesia. Mechanical and thermal hypersensitivity were evaluated 1 d before surgery (D-1), 4 h after surgery (D0), and for 3 d after surgery (D1, D2, and D3). In experiment 2, plasma buprenorphine concentration (n = 39) was measured at D0, D1, D2, and D3. Clinical observations were recorded daily, and a gross necropsy was performed on D3. Mechanical and thermal hypersensitivity were measured for 3 d (D0-D3) in the saline group. Bup-SR, XR-Lo, and XR-Hi effectively attenuated mechanical hypersensitivity for D0-D3. Plasma buprenorphine concentrations remained above 1 ng/mL on D0 and D1 in all treatment groups. No abnormal clinical signs were noted, but injection site reactions were evident in the Bup-SR (71%), XR-Lo (75%), and XR-Hi (87%) groups. This study indicates that XR-Hi did not attenuate hypersensitivity more effectivelythan did XR-Lo in this model. XR 0.65 mg/kg is recommended to attenuate postoperative mechanical hypersensitivity for upto 72 h in rats in an incisional pain model.

Effectiveness of two extended-release buprenorphine formulations during postoperative period in neonatal rats

“…In this current study, differences in thermal hypersensitivity testing on the contralateral thigh found in the Bup-SR, XR-Lo, and XR-Hi groups as compared to Saline group, at 1, 4, 8, and 24 h are likely due to sedation from the treatment drugs. Although sedation was not clinically evident in this study, it has been previously noted in the literature when administering Bup-SR or XR-Hi to rats [ 28 , 29 , 34 ].…”

“…Therefore, we decided to evaluate XR-Hi as compared to Bup-SR in neonatal rodents. Our group has found that XR-Hi effectively attenuates post-operative pain for 48 h in adult mice [ 25 ] and adult rats [ 28 ] using the plantar incisional model. Such a difference between Bup-SR and XR-Hi in the duration of attenuating pain may be attributed to the technological differences between the two drugs.…”

“…Analgesic dosages for neonatal pups should be adjusted to reflect the appropriate clinically effective dose for their age. Therefore, in this current study, to evaluate the safety, dosing, and efficacy of this new analgesic drug in neonatal pups, we also evaluated the low and high dose of XR-Hi which are efficacious for adult rats [ 28 ]. The XR-Lo group received the manufacturer’s recommended dose for rats (0.65 mg/kg) and the XR-Hi group received two times (1.3 mg/kg) the recommended dose.…”

“…Although in a previous study by our lab evaluating XR-Hi in adult mice, we did not find any gross pathologic abnormalities or injection site reactions [ 25 ]. A study by our lab investigated the effect of XR-Hi in adult rats and found subcutaneous nodules at the site of administration of XR-Hi and Bup-SR [ 28 ]. In this current study, although it was not clinically evident, we also found subcutaneous nodules at the time of gross pathological examination in the Bup-SR, XR-Lo, and XR-Hi groups.…”

“…Treatment groups consisted of: 1) Saline (Saline; 0.9% NaCl, Hospira, Lake Forest, IL) – 0.1 ml subcutaneous (SC) once ( n = 8), 2) Bup-SR (1 mg/mL)– 1mg/kg SC once ( n = 10), 3) XR-Lo (1.3 mg/mL) – 0.65 mg/kg SC once ( n = 10), 4) XR-Hi 1.3 mg/kg SC once ( n = 10). Doses of buprenorphine chosen were based on previous studies: 1) Bup-SR at 1 mg/kg was based on Blaney et al [ 20 ]; 2) XR-Hi at 0.65 and 1.3 mg/kg was based on doses in adult Sprague Dawley rats by Levinson et al [ 27 ] and Alamaw et al [ 28 ] (note that doses of XR-Hi in rat pups are not known).…”