Buprenorphine-induced hyperalgesia in the rat

In addition to analgesia opioids may also enhance pain sensitivity. Opioid-induced hyperalgesia, typically associated with potent mu-opioid agonists (e.g. fentanyl, morphine, and heroin), may be of clinical importance due to the possible counteraction of analgesia and/or paradoxical enhancement of a pre-existing pain condition during opioid therapy. Buprenorphine, a potent opioid analgesic, has a complex pharmacology on mu and kappa receptors. Buprenorphine has a better analgesia/toxicity profile (a ceiling effect for respiratory depression, less potential for abuse) compared to typical mu-opioids. Little is known about buprenorphine-induced hyperalgesia. Potentially, a lack of hyperalgesia with these other characteristics could make buprenorphine a more desirable opioid for management of chronic pain. Responsiveness to high and ultra-low doses of buprenorphine was examined following acute and repeated administration in a rat model of thermal nociception (the tail-flick test). Buprenorphine produced a dose-related antinociception. Loss of efficacy (tolerance) followed by enhanced pain sensitivity occurred with repeated dosing of buprenorphine. Delayed hyperalgesia, seen in association with antinociceptive tolerance, was blocked by the NMDA receptor antagonist, ketamine. Buprenorphine (ultra-low dose) resulted in immediate hyperalgesia, which was also reversed by ketamine, in a dose-related fashion. No tolerance to hyperalgesia was seen with repeated dosing of low-dose buprenorphine. The antinociceptive effect of buprenorphine was diminished in rats, which previously exhibited hyperalgesia with buprenorphine. In summary, bimodal properties of buprenoprhine were separately demonstrated: pronociceptive at ultra-low dose and antinociceptive at higher doses. An NMDA-receptor mechanism was involved in hyperalgesia with buprenorphine.