The precise management of postoperative pain in laboratory animals is pivotal for enhancing animal welfare and ensuring reliable experimental results. This research aims to refine the application of extended-release buprenorphine (Ethiqa), the only FDA-approved opioid for long-term analgesia in rats, to by counteracting unwanted side-effects. Despite and the advantage of the extended-release buprenorphine’s long duration of action, there are significant adverse effects from its post-operative administration, including pica behavior(the consumption of non-food substances) and compromised gastrointestinal (GI) motility. Preliminary studies have identified a substantial post-operative mortality rate linked to pica behavior following extended-release buprenorphine administration. There is an urgency for improved analgesic protocols that mitigate buprenorphine-associated morbidity and mortality, to improve both animal welfare and data recovery for the research team. Here, I propose a dual-pronged approach to refine pain management in Sprague-Dawley rats, addressing the adverse effects of extended-release buprenorphine: The first strategy involves inhibiting pica behavior through counteracting buprenorphine-induced activation of central emetic pathways, and the second strategy focuses on improving GI motility by targeting the peripheral effects of buprenorphine, which reduces GI function. I hypothesize that these adjustments in analgesic regimen will alleviate buprenorphine’s negative side effects while maintaining sustainable, long-term pain management, advancing animal welfare. The first aim seeks to attenuate pica behavior through the co-administration of the serotonin antagonist ondansetron with extended-release buprenorphine. I will employ quantitative measures such as kaolin consumption to assess pica behavior. The second aim is to enhance GI motility using bisacodyl, a stimulant prokinetic, along with extended-release buprenorphine to prevent associated GI complications. This will involve monitoring GI transit times and overall recovery post-treatment. The successful implementation of this research will align with the Three R's of animal research and will set a new standard in analgesic regimen.