Opioids: from analgesia to anti-hyperalgesia?

Nowadays, opioids are well recognized as unsurpassed analgesics for relieving severe acute and chronic pain. However, as previously suggested (Scholz and Woolf, 2002), clinical pain is not a monolithic entity limited to integration of nociceptive inputs but is associated with neuronal plasticity that by increasing pain elicits pain hypersensitivity might lead to pain pathogenesis. In other words, this means that treating pain may not be limited to the use of anti-nociceptive agents even if they are very potent like opioids, but an anti-hypersensitivity strategy per se should be also considered. On this issue, Koppert and colleagues report that buprenorphine, a partial m-receptor agonist and k-and d-receptor antagonist, exerts not only analgesic effects as classically described for opioids but also induces anti-hyperalgesic effects in a human model of electrically evoked pain and hyperalgesia (Koppert et al., 2005). Interestingly, buprenorphine's anti-hyperalgesic effects are more pronounced and have significant longer half-times as compared to antalgic effects. This long-lasting anti-hyperalgesia observed with intravenous and sublingual buprenorphine contrasts with the delayed and long-lasting hyperalgesia observed with several pure m-opioid receptor agonists in both animal models and clinical studies (Angst et al. Indeed, it has been previously reported that the larger the intraoperative opioid fentanyl or remifentanil doses, the greater is the postoperative pain level and morphine requirement (Guignard et al., 2000). It has been proposed that such a paradoxical phenomenon might account for exaggerated post-operative pain and acute tolerance after using them in surgery (Ossipov et al., 2003; Richebe et al., 2005; Simonnet and Rivat, 2003). Two classes of opioids may be distinguished independently of their analgesic potencies according to the current study of Koppert et al. A first class of pure m-opioid receptor agonists would induce undesirable long-lasting hyperalgesia and a second one would have anti-hyperalgesic properties. Interestingly, authors defined an anti-hyperalgesia/analgesia ratio with which analgesic drugs may be graded. Among opioids tested in this study, buprenorphine has the highest ratio. This new insight is probably predictive of future advances in opioid management of pain states dominated by central sensitization, e.g. exaggerated post-operative pain and some forms of chronic pain. Why so? Depending on whether pain sensation enhancement induced by nociceptive inputs is facilitated or not by some opioids, especially they are administered at large doses, we need to reexamine opioid profiles, not only for their own anti-nociceptive capacities but also for their ability to facilitate or prevent central pain sensitization. Based on recent …