Defining the pharmacology of sustained-release buprenorphine in acute and chronic pain states in various species

Abstract

Pain is a clinical syndrome arising from a variety of etiologies, which creates difficulty in successfully treating the individual patient. Sustained-release buprenorphine is widely used in a variety of species with the intention of providing long-lasting analgesia. Statements about duration of therapeutic efficacy are based on persistence of serum buprenorphine levels over a minimum threshold, but behavioral data demonstrating sustained efficacy is not established. Additionally, chronic opioid exposure can induce tolerance and/or hyperalgesia; many species receiving sustained-release buprenorphine have not been evaluated for these effects.This work reviews buprenorphine metabolism, opioid signaling, and pain models to establish the context for examining the clinical efficacy and duration of analgesia provided by a single subcutaneous administration of sustained-release buprenorphine at clinically-recommended doses in mice, rats, and cats under conditions of inflammatory pain (mice and rats), cancer pain (mice), thermal nociception (mice and rats), and post-operative pain (mice, rats, and cats). Mice and rats were also screened for development of opioid tolerance. In mice and rats, a single subcutaneous administration of sustained-release buprenorphine produced analgesia for hours rather than days, and subsequent administration of buprenorphine produced a decreased dose-response curve. In cats, ketoprofen offered as much or more analgesia after ovariohysterectomy under multi-modal anesthesia as sustained-release buprenorphine does, when assessed by spontaneous behavioral measures and by evoked reflexive measures. Based on assessments using evoked reflexive measurements in mice and rats, there is evidence that a single subcutaneous administration of sustained-release buprenorphine at clinically-recommended doses induces acute opioid tolerance in mice and rats, shortening the duration of antinociception. It is reasonable to suspect that a similar mechanism may occur in the cat leading to decreased analgesic efficacy in the post-operative period.