Sustained release buprenorphine effectively attenuates postoperative hypersensitivity in an incisional pain model in neonatal rats (Rattus norvegicus)

Abstract

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.

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

“…However, due to the small hind paw size of neonatal rats, we modified the incisional pain model and performed a skin incision with dissection of the underlying muscle on the left thigh to increase the area for post-operative hypersensitivity testing. Previous studies by our lab have indicated that the thigh incisional pain model induces a post-operative thermal hypersensitivity response for 4 to 8 h in neonatal rats [ 19 , 20 ]. Previous work indicated that a diode laser provides sufficient stimuli to cause a withdrawal reflex to evaluate thermal hypersensitivity in adult rats [ 33 ].…”

“…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).…”

“…All drug administrations were performed by the same personnel, who did not participate in subsequent testing or pathological evaluations, to ensure the tester is blinded to the treatment groups. The surgical method was adapted from Blaney et al [ 20 ] and was performed aseptically as required by the Stanford IACUC Guidelines for Rodent Survival Surgery. Briefly, the pups were positioned in right (contralateral) recumbency, and the left (ipsilateral) thigh was aseptically prepared with three alternating betadine solution swab sticks (10% povidone-odine, Dynare Corporation, Orangeburg, NY) and 70% Isopropyl Alcohol USP (Henry Schein, Melville, NY).…”

“…The skin temperature of both ipsilateral and contralateral side was 33.8 ± 0.1˚C. Baseline thermal hypersensitivity of 5-day-old pups was determined at -1 h with laser stimulation adapted from Blaney et al [ 20 ]. During stimulation and testing, two to three pups were evaluated at a time by maintaining them on a warm water circulating blanket (set at 38 ˚C) (Stryker T/Pump, Portage, Michigan, USA).…”

“…Opioid analgesics, including buprenorphine HCL (Bup-HCL, Hospira, Lake Forest, IL) and sustained-released buprenorphine (Bup-SR, Zoopharm, Fort Collins, CO), are the most commonly used analgesic drugs for managing post-operative pain in laboratory rodents [ 18 ]. In neonatal rats, a single dose of Bup-HCL (0.025 or 0.05 mg/kg) was found to effectively attenuate post-operative thermal hypersensitivity for 4 h [ 19 ], while a single dose Bup-SR (either 0.5 or 1 mg/kg) was found to effectively attenuate hypersensitivity for 8 h [ 20 ]. Recently, a new FDA-indexed, lipid-bound extended-release buprenorphine (XR-Hi, Ethiqa®, Fidelis Animal Health, North Brunswick, NJ) was introduced as an alternative buprenorphine analgesic for rodents.…”