No hyperalgesia following opioid withdrawal after the oripavine derivative etorphine compared to remifentanil and sufentanil

BACKGROUND AND OBJECTIVE: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure. METHODS: To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated. RESULTS: Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of R43 and R17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was R9%, whereas heart rate still remained below S9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by R70% after remifentanil and by R43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below S80% when compared with control. CONCLUSION: The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.