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Postoperative Analgesia of Sustained-Release Buprenorphine, SustainedRelease Meloxicam, and Carprofen Gel in a Model of Incisional Pain in Rats (Rattus norvegicus) 1* Seymour , 1 Adams , 1 Felt , 3 Jampachaisri , 2 Yeomans , 1 Pacharinsak Travis L. Sean C. Stephen A. Katechan David C. Cholawat 1 2 3 Departments of Comparative Medicine and Anesthesia, Stanford University School of Medicine, Stanford, CA; and Department of Mathematics, Naresuan University, Phitsanulok, Thailand Abstract Postoperative analgesia is a vital aspect of laboratory animal medicine. Novel analgesic formulations of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) have recently been introduced to the laboratory animal market. The aim of this study is to investigate whether postoperative analgesia of sustained-release buprenorphine (Bup-SR), sustained-release meloxicam (Melox-SR), or carprofen gel (CG) is effective to control mechanical and thermal hypersensitivity in a model of incisional pain in rats. Mechanical and thermal hypersensitivity were tested daily from day -1 to 4. Rats were randomly placed into 5 treatment groups: 1) saline (0.9% NaCl, 1 ml/kg SC twice daily, days 0 to 3); 2) BupHCl (0.05 mg/kg SC twice daily, days 0 to 3); 3) Bup-SR (1.2 mg/kg SC once before an incision); 4) Melox-SR (4 mg/kg SC once before an incision); 5) CG (1 cup daily from days -2 to 2). Mechanical hypersensitivity was attenuated in all treatment groups on days 1-4. Thermal hypersensitivity was attenuated in Bup-HCl and Bup-SR groups, but not in Melox-SR or CG groups, on days 1-4. These findings suggest that postoperative analgesia of Bup-SR, but not Melox-SR or CG, is effective to attenuate mechanical and thermal hypersensitivity in a model of incisional pain in rats. Introduction Many surgical procedures performed in rats cause postoperative pain for at least 48 hr, requiring personnel to handle the animals frequently. Bup-HCl, a partial μ-opioid receptor agonist, is considered the “gold standard” and has been widely used for postoperative analgesia for many surgical procedures in laboratory rats due to its long plasma half-life and effective postoperative analgesia. Due to its duration of action, it should be administered q 6-12 hrs; repeated dosing results in handling-associated stress which can significantly alter animal physiology and research data. Numerous novel formulations of opioid (sustained-release buprenorphine) and NSAID (sustainedrelease meloxicam or carprofen gel) analgesics have been recently brought to the laboratory animal market; many without published efficacy studies. Due to their longer duration of action and formulations, they may offer significant refinements to laboratory animal care. AIM: To investigate whether postoperative analgesia of sustained-release buprenorphine (Bup-SR), sustainedrelease meloxicam (Melox-SR), or carprofen gel (CG) is effective to control mechanical and thermal hypersensitivity in a model of incisional pain in rats. [1] Brennan TJ, Vandermeulen EP, Gebhart GF. 1996. Pain 64: 493-501. Methods Animals: Thirty-three adult male Sprague Dawley rats weighing 350-400 gm. Results * Indicates significance (P < 0.05) compared with day -1 Surgical incision: Rats were anesthetized with isoflurane (day 0). The incisional pain model was performed on the plantar surface of the left hindpaw (ipsilateral) of each rat based on a previously established model [1]. Rats recovered from surgery for 1 day prior to behavioral testing. Drug administration and experimental groups: Rats were assigned to 1 of 5 treatment groups: Bup-SR (1.2 mg/kg SC once before an incision); Melox-SR (4 mg/kg SC once before an incision); CG (1 cup daily from days -2 to 2); Bup-HCl (0.05 mg/kg SC twice daily, days 0 to 3); control (0.9% NaCl, 1 ml/kg SC twice daily, days 0 to 3). Rats underwent mechanical and thermal hypersensitivity testing once daily on day -1 and 1-4. Behavioral Testing • Mechanical hypersensitivity (no. of foot raises): Rats were placed in a clear plastic chamber. Von Frey monofilaments with calibrated bending forces were used to deliver punctate mechanical stimuli (10 g force). No. of foot raises evoked by Von Frey monofilaments were obtained for 10 consecutive trials for each hindpaw. Mechanical hypersensitivity was defined as a significant increase in foot raise frequency evoked by Von Frey monofilaments. The right hindpaw (contralateral) served as a control. • Thermal hypersensitivity (thermal latency): Rats were placed in a clear plastic chamber. A 50 W light bulb was focused on the middle of the plantar surface of each hindpaw for 4 consecutive trials. Thermal (paw withdrawal) latency (s) was measured as the mean of the last 3 trials. Thermal hypersensitivity was defined as a significant decrease in paw withdrawal latency evoked by thermal stimuli. The right hindpaw (contralateral) served as a control. Figure 2. Ipsilateral hindpaw: Mechanical hypersensitivity was attenuated in all treatment groups on days 1-4. * Indicates significance (P < 0.05) compared with day -1 Statistical Analyses: Mean withdrawal responses were analyzed using repeated-measures ANOVA with Bonferroni correction for multiple comparisons to examine differences in withdrawal responses between groups and over time. Data were expressed as mean ± SEM. A P value of less than 0.05 was considered significant. Figure 3. Ipsilateral hindpaw: Thermal hypersensitivity was attenuated in Bup-HCl and Bup-SR groups, but not in Melox-SR or CG, on days 1-4. Conclusions These findings suggest that postoperative analgesia of Bup-SR, but not Melox-SR or CG, is effective to attenuate both mechanical and thermal hypersensitivity in a model of incisional pain in rats. Acknowledgments Funding was provided by the Department of Comparative Medicine, Stanford University School of Medicine. Figure 1. Timeline of surgical procedure, behavioral testing, and drug administration. Contact: [email protected]